Endocrinology and Immunology of Acne

Endocrinology and immunology of acne: Two sides of the same coin
Christos C. Zouboulis
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Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical
Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany
Funding: None
Conflict of interest: C.C. Zouboulis has received thematically relevant honoraria from Bayer
Healthcare and PPM as advisor and conference speaker, from Allergan and Almirall as advisor,
and from Jenapharm as conference speaker, which have no influence on the preparation of this
manuscript.
Word count: 6438

Number of references: 202
Tables: 2
Figures: 14
Corresponding author: Prof. Dr. Christos C. Zouboulis, Departments of Dermatology,

Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical
School Theodor Fontane, Dessau, Germany, Auenweg 38, 06847 Dessau, Germany
Tel: +49 340 5014000 – Fax: +49 340 5014025
E-mail: christos.zouboulis@mhb-fontane.de
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/exd.14172
This article is protected by copyright. All rights reserved
ABSTRACT
Current experimental research on acne pathophysiology has revealed a more complicated template
than the classically reported four factor etiology. Cells of the pilosebaceous unit, which represent
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the template for the developments of acne lesions seem to be parallelly affected by
endocrinological/metabolic factors as well as inflammatory/immunological ones, which influence
cooperate in sebocyte differentiation/lipogenesis, holocrine secretion and sebum production.
Indeed, the unique programme of sebocyte terminal differentiation and death, the so called
holocrine secretion, is influenced by inflammatory and metabolic (lipid) signaling with common
denominator the selective regulation of peroxisome proliferator-activared receptors. Autophagy
provides substrates for energy generation and biosynthesis of new cell structure proteins
contributing to the normally increased sebaceous gland metabolic functions, which are also
regulated by extracellular calcium signaling, essential lipids and hormones. The ultimate
differentiation product of human sebocytes, sebum, co-regulates the inflammatory sebocyte status.
Sebum composition is controlled among others by Propionibacterium acnes and other bacteria,
sexual hormones, neuropeptides, endogenous opioids and environmental agents, which may
function as endocrine disruptors. Diet may also be an important source of substrate for the
synthesis of proinflammatory and antinflammatory sebaceous lipids. Sebum changes might induce
inflammation and initiate underlying immune mechanisms leading to acne lesions. Current new
therapeutic efforts on acne concentrate on anti-inflammatory/immunologically active concepts,
which are able to regulate sebaceous lipogenesis. At last, current molecular studies based on
published molecular datasets confirmed the major role of inflammation in acne development.
Keywords: Acne, Sebaceous gland, Inflammation

INTRODUCTION
Although acne vulgaris is one of the most common human diseases [1], many questions regarding
its exact pathogenesis, classification and treatment still remain unanswered. The classical four-
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factor acne pathogenesis has been modified through continuous research over the years to a more
complicated template, namely a disturbed sebaceous gland activity associated with
hyperseborrhoea [1, 2] and alterations in sebum fatty acid composition [2], dysregulation of the
hormone microenvironment [3], interaction with neuropeptides [4], aberrant differentiation of the
follicular epithelium and follicular hyperkeratinization [5], induction of inflammation [6] and
dysfunction of the innate and adaptive immunity [7]. These processes impair the function of the
pilosebaceous unit, which leads to the transition of a normal follicular canal to microcomedone,
and further to a comedone and inflammatory lesion [1] (Fig. 1).
SEBOCYTE DIFFERENTIATION, HOLOCRINE SECRETION AND LIPOGENESIS

The human sebaceous gland is a multiacinar, exocrine organ [8]. It is structured - from its
periphery to the center - of undifferentiated, differentiating and mature sebocytes [9], which burst
and die releasing their content to the sebaceous duct and subsequently to the associated follicular
canal. The average transit time of human sebocytes from formation to discharge is approximately
3-4 weeks, with 4-7 days in undifferentiated and 14-25 days in differentiated lipid-producing
stages [8]. Sebocyte terminal differentiation and death consists a unique procedure called
holocrine secretion, which represents a multi-step, cell-specific lysosomal DNase2-mediated mode
of programmed cell death [10-12]. Moreover, it is determined by the release of histone-associated
DNA fragments controlled by p44 ⁄42 and protein kinases ⁄Akt [13,14]. The lipid ligands
peroxisome proliferator-activated receptor (PPAR)β is also involved in sebocyte apoptosis [14]. In
contrast to its family members PPARα and γ, it seems to stimulate sebocyte proliferation and
inhibit terminal differentiation and apoptosis, a property that may be beneficiary in acne [14,15].
In addition to their differentiation-associated polarization towards the gland center, sebocytes are
equipped with tight junction (TJ) barriers orchestrated by claudin-1, whereas holocrine secretion
occurs outside the TJ barrier. Claudin-1 knockout induces leakage of the TJ barrier and impaired
holocrine secretion, resulting in stack formation of incompletely degenerated sebocytes within the
pilosebaceous ducts and microcomedo formation [16], suggesting that skin inflammation may
cause the TJ barrier of sebaceous gland to leak, triggering the development of acne lesions.
Interestingly, mature sebocyte cell death in animal and human sebaceous glands is followed by

active autophagy in order to provide substrates for energy generation and biosynthesis of new cell
structure proteins contributing to normal sebaceous gland function [17,18]. Inhibition of
autophagy in animal sebocytes was associated with a 40% reduction in the proportion of free fatty
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acids (FA) and cholesterol, and a 5-fold increase in the proportion of FA methyl esters [17],
changes that are compatible with sebum composition alterations detected in acne patients [2].
CALCIUM SIGNALING AND SEBOCYTE DIFFERENTIATION

The transient receptor potential channel V3 (TRPV3) is expressed in human sebocytes. Its
activation by TRPV3 agonists, such as 2-aminoethoxydiphenyl borate and carvacrol, which evoke
intracellular Ca2+ signals, inhibits arachidonic acid (AA)-enhanced, endocannabinoid (anandamide)-
enhanced as well as testosterone and linoleic acid (LA)-enhanced sebaceous lipogenesis and
stimulates sebaceous inflammatory signaling, i.e. induction of interleukin (IL)1α, IL1β, IL6, IL8
and tumor necrosis factor (TNF)α secretion [19]. Indeed, a marked effect of Ca2+ signaling on
sebocyte differentiation and apoptosis has been reported, which can be controlled by vitamin D
[20]. Intracellular Ca2+ signaling can also be modified by nicotinic acid (NA) activation of the
hydroxycarboxylic acid receptor-2, which is also expressed in human sebocytes, leading to
normalization of the acne‐mimicking, excessive sebaceous lipogenesis induced by AA,
anandamide [19] as well as testosterone and LA [21]. Although NA can reduce sebaceous gland
enlargement and even induce skin dryness, is not involved in regulating the accompanying pro-
inflammatory response. Interestingly, NA also exhibits an antiproliferative effect on human
sebocytes, whereas both its activities on sebocyte proliferation and differentiation are mediated
through intracellular Ca2+ alterations.
SEBUM AND ACNE

Increased sebum excretion, alteration of lipid composition and the oxidant/antioxidant ratio
characteristic of the skin surface lipids are major concurrent events associated with the
development of acne [22,23]. Interference of sebum with the process of follicular keratinization in
the pilosebaceous unit leads to follicular canal blockage, which contributes to lesion formation and
acne. However, seborrhoea per se is not considered to be the only responsible factor for the
development of acne, as demonstrated by the success of treatment with agents with no effect on
sebum secretion rate that can inhibit the inflammatory process, such as antibiotics, topical
retinoids, azelaic acid and benzoyl peroxide [1,24]. The composition of the produced lipids is also

of great importance [2] (Fig. 2). Lower essential FA levels were found in wax esters in twins with
acne rather than in twins without acne [25]. Moreover, low LA levels have been detected in skin
surface lipids of acne patients [26]. Evidence suggests that diet may be an important source of
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substrate for the synthesis of sebaceous lipids [27]. This notion is also supported by the
observation that sebum contains LA, which an essential FA that cannot be synthesized in vivo and
therefore must be provided by the diet. Other studies have demonstrated that increased
consumption of dietary fat or carbohydrate increases sebum production and alterations of
sebaceous lipid composition [28]. Typical western diet, comprised of milk and hyperglycaemic
foods, may have potentiating effects on serum insulin and insulin-like growth factor-1 (IGF1)
levels, thereby been considered to promote the development of acne [29]. However, normal diet
barely leads to abnormally high serum IGF1 levels [30] and, therefore, the IGF1 pathway seems to
barely lead to induction of acne lesions under normal dietary habits.
Another hallmark of sebum in acne patients might be its content in lipoperoxides, mainly due to
the peroxidation of the sebaceous gland specific lipid squalene by keratinocytes [31] and a
decrease in the level of vitamin E, a sebum antioxidant [32]. Lipoperoxides and monounsaturated
FA affect keratinocyte proliferation and differentiation, whereas lipoperoxides increase the levels
of pro-inflammatory cytokines and activate PPARα and γ. The resulting ligand-receptor
complexes activate pathways involving sebocyte proliferation, differentiation, lipogenesis,
hormone metabolism and cytokine and chemokine release [14,23,33] (Fig. 3).
Considering that free FA are also a major component of sebum, it is likely that changes in free FA
concentration can affect both the synthesis of sebum as well as the inflammatory response in
sebaceous glands [2,34-36]. Like AA and LA [37,38], palmitic acid was also shown to increase
the levels of sebum lipids that are contained in the sebum in vitro and in vivo [39]. Free FA
become incorporated into wax esters and other neutral lipids, which are synthesized solely by the
sebaceous gland [40]. In addition, free FA significantly increased the levels of proinflammatory
cytokines in human sebocytes [15,36-39]. The increased secretion of IL6 and IL8 after sebocyte
treatment with free FA may be an important link to acne as both these cytokines have been shown
to contribute to the formation of acne lesions [2,15,39-41]. Regulation of stearoyl-CoA desaturase
and fatty acid desaturase 2 expression by linoleic acid and arachidonic acid in human sebocytes
leads to enhancement of proinflammatory activity but does not affect lipogenesis [38]. At last,

Toll-like receptor (TLR)-2 and TLR4 on sebocyte surface (Fig. 4) are activated by exogenous FA
and lead to IL6 and IL8 synthesis and release from human sebocytes [34,40,42], suggesting an
aetiologic of increased sebum production and lipid dysregulation in initiation and/or aggravation
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of inflammatory processes during acne pathogenesis [2,43].
Like adipocytes, human sebocytes produce adipokines, which among their functions, also control
lipogenesis [44]. Moreover, current research has detected a large number of new molecules, which
can regulate sebaceous lipogenesis in homeostatic stage and in disease, a fact that makes the
understanding of sebaceous fraction modifications in acne and its background more complicated
than ever [2,45-54].
HORMONES AND ACNE

Hormones exert their biological effects on the cells of the pilosebaceous unit through binding and
interaction with high-affinity receptors [22,23,55-57]. Human sebocytes express receptors for
peptide hormones and neurotransmitters, which are mostly aligned on the cell surface, and those
for steroid hormones, which are found in the cytoplasm or nuclear compartments [55,56]. In
addition to their capacity to respond to hormone signals the cells of the pilosebaceous unit are able
to metabolize hormones in order to activate and inactivate them [57-59]. Characteristic examples
for this kind of cutaneous endocrine function are the metabolic pathways of the sexual steroids and
retinoids [60]. Abnormal modifications of hormone signaling pathways can initiate pilosebaceous
unit alterations leading to acne lesions.
Insulin-like growth factor-1 is involved in the development of acne

Since more than two decades the paracrine insulin-like growth factor-1 (IGF1) is known to be an
important hormone for epithelial skin homeostasis [61] and appendage development [62].
Moreover, acne severity has been linked with IGF1 serum levels [29,30,63]. IGF1 stimulates the
export of the nuclear transcription factor FoxO1 out of the nucleus into the cytoplasm via
activation of the phosphoinositol-3-kinase (PI3K)/Akt pathway [64] (Fig. 1). In addition, IGF1
regulates sterol regulatory element-binding protein-1 (SREBP1) levels in human sebocytes [65], a
protein that regulates lipid, especially cholesterol, metabolism [66]. Increased IGF1 levels in acne
are correlated with the promotion of mammalian target of rapamycin (mTOR) signaling [45,67,68].
mTOR complex 1 has a crucial role in the PPARγ-stimulated lipid uptake and differentiation of

sebocytes, while at the same time promoting lipid production by activating SREBP1 [44,69].
Through this mechanism, the genes and nuclear receptors involved in acne are diminished, leading
to increased androgen receptor-mediated signal transduction, increased sexual hormone-regulated
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sebocyte proliferation and induction of sebaceous lipogenesis [70-74]. Androgens only induce the
phosphorylation of mTOR in human sebocytes in the presence of IGF1 [68], suggesting that local
active androgen production with circulating IGF1 has a pivotal role in sebum synthesis and acne
[71] (Fig. 2).
Regarding sebaceous lipogenesis and inflammation, insulin and IGF1 stimulate the formation of
unsaturated lipids and then the neo-lipogenesis in human sebocytes [66]. Among the mono-
unsaturated fatty acids [67], the acne-associated C16:1 appears to be the most influenced [27].
C16:1 levels are associated with acne severity. Regarding sebocyte proliferation, insulin and IGF1
reduce p21 protein expression and subsequently increase the cell number at the S phase of the cell
cycle. PPARγ, and its target genes ADRP, encoding adipophilin, and angiopoietin-related gene
(PGAR), which regulates lipogenic pathways and sebaceous lipogenesis at protein and mRNA
level, are expressed at lower levels in sebaceous glands in both involved and non-involved skin
from acne patients associated with the increase in endogenous lipid ligands, i.e. eicosanoids [75].
The basal level expression of genes and proteins involved in insulin- / IGF1-induced lipogenesis,
proliferation and inflammation are significantly higher in sebocytes with reduced or abolished
PPARγ expression, suggesting the involvement of this nuclear receptor in the control of cellular
physiological processes [69,70,76]. On the other hand, chronic inflammatory response has a
critical role in the development of acne [1,24]. IGF1 has been shown to regulate in vitro cytokine
expression in professional inflammatory cells and to stimulate TNFα, IL6, and IL8 secretion in
human sebocytes [69,77,78].
Sexual hormones
Several functions of the human skin appear strongly dependent on biologically active sexual
hormones, namely androgens, estrogens, and progestins [79,80]. Human skin is not only the target
of androgens, but sebocytes can also synthesize androgens in situ [58]. Although human sebaceous
glands can produce testosterone by de novo synthesis from abundant serum cholesterol [81],
testosterone synthesized in cultured sebocytes is derived mainly via a shortcut pathway by using
circulating dehydroepiandrosterone (DHEA) [82]. DHEA has a weak androgenic effect but is a

precursor hormone that is further metabolized into potent androgens and estrogens. A rise in
androgen levels, like in puberty, might lead to acne due to elevated lipogenesis/sebum synthesis in
sebocytes, changes in skin cell activity, inflammation, and colonization of the hair follicles by
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Propionibacterium acnes (P. acnes; also termed C. acnes by some authors) [79,80]. Certain
steroidogenic enzymes, such as 11β-hydroxysteroid dehydrogenase, are expressed in the
sebaceous glands and upregulated in acne lesions [59].
Genetic variation of steroid hormones and acne

Genetic studies indicate that regulation of the androgen receptor is an important factor in severe
acne. In women, non-classic adrenal hyperplasia is associated with hyperandrogenic
manifestations, such as severe acne refractory to treatment, hirsutism, androgenic alopecia or
seborrhea, as well as irregular menses and polycystic ovaries. Glucocorticoids also regulate the
production of sebum. Enzymes catalyzing the conversion of cortisone to active cortisol are highly
expressed in keratinocytes, fibroblasts and sebaceous glands, and are upregulated in acne lesions
[83]. In human sebocytes, dexamethasone treatment enhances lipid synthesis, partially through the
transcriptional induction of sterol regulatory element-binding transcription factor 1 (SREBF1,
which encodes SREBP1) and by increasing TLR2 mRNA levels [69].
Neurohormones and acne

Neuropeptides, hormones and cytokines act as signaling molecules that mediate communication
between the three interacting systems [84]. Analogous to central responses to stress, which involve
predominantly the hypothalamic–pituitary–adrenal (HPA) axis, the skin may share similar
mediators [85,86]. On the other hand, psychoemotional stress, which may induce the development
of clinical inflammation in the pilosebaceous unit, is one of the confirmed pathogenetic aspects in
acne vulgaris [4,87,88]. Activation of the HPA axis with release of stress neuropeptides is
essential for biological homeostasis and responses to external and internal challenges.
Innervation of the human sebaceous gland is yet to be conclusively confirmed. Numerous

substance P immunoreactive nerve fibres and mast cells were detected in close apposition to facial
sebaceous glands of acne patients and stronger expression of the substance P-inactivating neutral
endopeptidase within the sebaceous germinative cells of their sebaceous glands [89]. In vitro
experiments using an organ culture system demonstrated that substance P induced expression of

neutral endopeptidase in sebaceous glands in a dose-dependent manner [89]. Neutral
endopeptidase belongs to the group of ectopeptidases, which are expressed in the sebaceous glands
and may initiate an inflammatory signaling compatible with initiation of comedogenesis [90].
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Sebaceous glands express receptors for several neurohormones [4,84]. After ligand binding,
neuropeptide receptors modulate the production of inflammatory cytokines, proliferation,
differentiation, lipogenesis and androgen metabolism in acne-inolved sebocytes. By means of their
autocrine, paracrine and endocrine actions, these neuroendocrine factors appear to mediate
centrally and topically induced stress towards the sebaceous gland, ultimately affecting the clinical
course of acne [4,84,88,91,92].
Treatment of sebocytes with IL1β, which results in marked increase of IL8 release, was partially
blocked by co-incubation of the cells with α-melanocyte-stimulating hormone (αMSH) in a dose-
dependent manner [93]. IL6 and IL8 are abundantly expressed in acne-involved sebaceous glands
and might be involved in the development of acne lesions [15]. Their release by sebocytes can be
induced by the upstream hypothalamic neuropepride, corticotropin-releasing hormone (CRH),
through an IL1β-independent pathway [94]. CRH also induces the synthesis of sebaceous lipids in
vitro [95]. Both αMSH and CRH are expressed in sebaceous gland cells in vivo and are
upregulated in acne-involved sebaceous glands, influencing the feedback regulation, which occurs
during the induction of clinical inflammation in early acne lesions [92,96].
Endogenous opioids and cannabinoids in acne

β-Endorphin, a propiomelanocortin-derived peptide and member of the endogenous opioid family
of neuropeptides, has sebotropic activity. The μ-opioid receptor, which binds β-endorphin with
high affinity, is expressed by the human sebaceous gland cells ( M. Böhm, Z. Li, M. Ottaviani, M.
Picardo, C. C. Zouboulis, J. Invest. Dermatol. 2004, 123, A10). β-Endorphin inhibits sebocyte
proliferation and stimulates lipogenesis and specifically increases the amount of C16:0, C16:1,
C18:0, C18:1 and C18:2 FA to an extent similar to LA. On the other hand, endocannabinoids
regulate sebocyte biology and also enhance lipogenesis in human sebocytes via a cannabinoid
receptor-2-mediated signaling [97,98]. Phytocannabinoids exert differential regulation of human
sebocyte differentiation but a common effective inhibition of cutaneous inflammation [99]. The
major nonpsychotropic phytocannabinoid of Cannabis sativa, cannabidiol, might exert anti-acne
effects because it inhibits lipogenesis [100].

Endocrine-disrupting chemicals, smoking and acne
Hormone-like effective compounds, e.g., hydrocarbons, aryl hydrocarbon receptor (AhR)-
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upregulating agents, compounds of plastics and dioxins, especially lipid-soluble compounds
among them, are defined as endocrine-disrupting chemicals (EDC) [101]. EDC can be classified
according to their origin, including natural and artificial hormones (e.g. phytoestrogens), drugs
with hormonal side effects, industrial and household chemicals, and side products of industrial and
household processes (Table 1). They are exogenous compounds that have the ability to disrupt the
production and actions of hormones through direct or indirect interaction with hormone receptors,
thus acting as agonists or antagonists [102]. They perturb the endocrine system and may induce
inflammatory and immunologic skin diseases, among them chloracne [103,104], through
activation of the AhR signal pathway [1045]. AhR negatively regulates lipid synthesis and
sebocyte differentiation and modulates the expression of TNFα and IL8 in human sebocytes via
the MyD88-p65 nuclear factor (NF)-κB/p38 MAP kinase (MAPK) signaling pathways [106,107].
Among EDC, 2,3,7,8-tetrachlorodibenzo-p-dioxin affects the differentiation of sebaceous gland
cells by switching human sebaceous into keratinocyte-like differentiation and inducing an
inflammatory/immunological reaction [108], also affecting cytochrome P4501A1 in epithelial skin
cells [109], also leading to scarring-like acne after ingestive poisoning [110]. Similar effects have
been attributed to nicotine and benzopypene, a polycyclic aromatic hydrocarbon resulting from the
burning of cigarette paper, in vitro [111-113], whereas smoking is inducing scarring acne in adult
women, confirming the experimental data [114]. At last particles in air polluted environment were
also detected to affect sebaceous lipogenesis [115].
FOLLICULAR DIFFERENTIATION AND ACNE

The beginning of micro-comedone formation is associated with aberrant differentiation of the
follicular epithelium [116,117], vascular endothelial cell activation and inflammatory events [118],
which supports the hypothesis that acne may represent a genuine inflammatory disease [6,119].
The identification of upstream mechanisms leading to the characteristic clinical lesions, the
comedones, which also seem to represent a sign of follicular inflammation, supports this
hypothesis. As postulated by the “comedone switch” hypothesis, comedones most likely arise
because of abnormal differentiation of infundibular cells [120,121]. Recent studies, including the
identification of Notch and keratin 79 as key players of infundibular differentiation and

homeostasis in mouse hair follicles [122], indicate that sebaceous gland lobes, serviced by own
dedicated stem cell populations, are recipients of dual counteracting effects, which regulate the
proliferation/differentiation equalibrium. Interestingly, the apparent initial step of comedogenesis,
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i.e. a perifollicular compartmentalization of skin-resident innate lymphoid cells as shown in the
wild-type C57BL/6 mouse, is dependent on edocrine sebaceous gland factors [123]. In addition,
sebaceous gland-released tumor necrosis factor/lymphotoxins lead the Notch signaling-associated
sebocyte growth limitation and control the differential synthesis of sebaceous lipid fractions and
establishment of a resident microbiome. These results corroborate previous reports that innate
immunity and sebaceous glands are directly regulating each other’s homeostasis [124].
P. ACNES, SEBACEOUS LIPOGENESIS, INFLAMMATION AND THE UNDERLYING

INNATE/ADAPTIVE IMMUNE MECHANISMS
P. acnes has been considered over decades to be primarily responsible for the development of acne
and antibiotics were consequently the first line treatment with a series of subsequent problems,
such as bacterial resistance [125]. However, bacterial resistance does not markedly reduce
antibiotic effectiveness in acne, since antibiotics retain their activity by exhibiting anti-
inflammatory para-antibiotic effects [1]. The increased amount of sebum, but especially the
alteration of its composition, stimulates the growth of P. acnes in the follicles [2], which requires
in addition the development of biofilm in order to grow properly [126]. In the majority of P.
acnes-positive acne patients, hair follicles are colonised by P. acnes macrocolonies/biofilms, but
follicular inflammation is not directly linked to cellular immune response [127]. Indeed, P. acnes
induces inflammatory response around the pilosebaceous unit through the secretion of
proinflammatory lipids and various cytokines, mostly leading to disease aggravation. P. acnes,
under environmental conditions that favor fermentation, produces short-chain fatty acids, which
drive inflammatory gene expression in human sebocytes in vitro [128]. Interstingly, exposure of
sebocytes to the stress-inducing catecholamines epinephrine and norepinephrine stimulated the
effect of P. acnes on sebaceous lipogenesis, but did not affect its cytotoxic or inflammatory
potential [129]. In an in vitro acne-like model, P. acnes also induced increased expression of
several proteins, among them the proinflammatory cytokine macrophage-inflammatory protein-2,
fibrinogen, α polypeptide, fibrinogen β chain, S100A9 and the serine protease inhibitor A3K
[130].

The mechanisms of inflammation induction in acne are complex. Acne sebaceous glands also
express enhanced levels of cyclooxygenase-2 (COX2) leading to increased prostaglandin E2
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(PGE2) levels, which cause sebaceous gland hyperplasia and overshooting sebum production
[15,43,131]. Human sebocytes express functional platelet-activating factor receptors, which are
involved in regulating the expression of inflammatory mediators, including COX2, PGE2 and IL8
[132]. PGE2 production in human sebocytes induced through oxidative stress involves PPARγ
[133]. Prostaglandins have been shown to influence sebocyte behavior through two distinct
mechanisms: the inhibition of histone deacetylase (HDAC) activity and the activation of fatty acid
receptors. Depletion of HDAC in human sebocytes results in an enhanced cytokine response to
TLR2 activation that resembled the transcriptional profile of an acne lesion [128]. P. acnes
reduces HDAC expression, induces p38 MAPK, enhances cytokine response to TLR2 and leads to
a significant amplification of macrophage-activating lipopeptide-2 (MALP2)–mediated induction
of IL1β, IL6, IL8, and CXCL10 in human sebocytes [128,134]. MALP2, which is an unspecific
bacterial antigen and selective TLR2/6 ligand (Fig. 4), directly induces high levels of IL6 and IL8
secretion by human sebocytes [34]. Local cytokine production can induce follicular keratinocyte
proliferation [24,117,135,136] (Fig. 5), leading to the initiation of acne with the development of
closed comedones and the attraction of professional inflammatory cells [23,119] (Fig. 6). In
addition, locally released TNFα by inflammatory cells induces sebaceous lipogenesis through the
JNK and PI3K/Akt pathways, but does not activate PPAR [137].
Furtheron, stimulation of human sebocytes with P. acnes activates the caspase-1 and leads to
secretion of IL-1β from human sebocytes in vitro [135,136]. The innate immune system
recognizes pathogens via pattern recognition receptors (Fig. 7), such as TLR and Nod-like
receptors (NLRs). Activation of nucleotide-binding oligomerization domain, Leucine rich Repeat
and Pyrin domain containing (NLRP)3, a nucleotide-binding oligomerization domain-like receptor,
by P. acnes in mouse skin and human sebocytes [136], dependent on protease activity and reactive
oxygen species generation, indicates that human sebocytes are important immunocompetent cells
that induce the NLRP3 inflammasome (Fig. 8). NLRP3-deficient mice as well as suppression of
the NLRP3 inflammasome by licochalcone A were shown to display an impaired inflammatory
response to P. acnes [137,138]. An agonist peptide for the protease-activated receptor-2, which
functions as innate biosensor for proteases expressed in sebaceous glands in acne [130,139],

enhanced lipogenesis and SREBP-1 expression, induced cytokines and β-defensin-2 (hBD-2)
transcription in cultured sebocytes suggesting that a role of sebaceous glands in the immunological
regulation of acne lesions. Complement C3, galectin-3-binding protein and neutrophil gelatinase-
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associated lipocalin were among the top 5 secreted sebocyte proteins [140] and the detection of
demcidin expression in LA-treated human sebocytes [141] and the expression of NF-κB signaling
induced by leptin through modification of sebaceous lipogenesis [142,143] indicate an important
role of sebaceous glands in the innate immunity of the skin through the expression of
antimicrobial peptides and specific lipids (Fig. 9).
P. acnes does not only exhibit pro-inflammatory properties [144]. It also enhances de novo
intracellular synthesis of triacylglycerols in human and hamster sebocytes in vitro through
activation of 15-deoxy-Δ(12,14)-prostaglandin J2, a cytochrome P450-linked sebaceous lipogenic
factor with anti-inflammatory properties [145]. Moreover, sebum free FA exhibit antibacterial
properties [146-148] and enhance the innate immune defense of human sebocytes by upregulating
antibacterial peptides [149], among them hBD2, cathelicidin as well as superoxide dismutase 3
[35,150,151].
Moreover, sebum FA have been shown to potently induce alternative macrophage activation,
which is the characteristic activation pathway for macrophages involved in tissue homeostasis and
repair functions [152]. They also increased macrophage phagocytosis of bacteria, including P.
acnes and they exhibited a differential effect on the inflammatory response of P. acnes-activated
macrophages [36].
At last, sebocytes participate in skin inflammation by recruiting and communicating with

professional immune cells, an interaction, which leads to the generation and differentiation of
Th17 cells [7]. This fact indicates possible common induction of proinflammatory pathways with
other inflammatory skin diseases, such as hidradenitis suppurativa and psoriasis. The capacity of
sebaceous glands to modulating innate immune responses through lipogenesis is of possible major
pathological and therapeutic relevance regarding acne [36] (Fig. 10). Moreover, genome wide
analysis of TLR2- and TLR4-activated human sebocytes presented a complex immune-
competence of activated sebaceous glands [153]. Human acne-involved sebaceous glands were,
indeed, shown to express common molecules (psoriasin, CRABP-II, CYP26AI) with other

inflammatory diseases, such as psoriasis and lichen ruber [154].
NEW ASPECTS OF ACNE TREATMENT

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The vast majority of ongoing acne treatment studies concentrates consequently on combinations of
endocrinological/metabolic and inflammatory/immunological aspects of the disease.
Isotretinoin revisited
Isotretinoin, the most powerful anti-acne drug [155-157], seems to exhibit more complex effects
on the sebaceous gland than initially postulated [158] (Table 2). Among other pathways, protein
domains for collagen and fibronectin were increased, domains for steroid metabolizing enzymes
were decreased, the mRNA levels of cellular retinoic acid-binding protein 2, S100A2, S100A7,
S100A9, and involucrin were affected and pathways linked to lipid metabolism were
downregulated [159,160]. Isotretinoin induces sebocyte cycle arrest and apoptosis by a RAR-
independent mechanism, which contributes to its sebosuppressive effect [161]. Selective
isomerization of isotretinoin to tretinoin in the intracellular compartment of human sebocytes, a
reduced tretinoin inactivation process after isotretinoin administration as compared to treatment
with tretinoin, a retinoic acid receptors-mediated inhibition of sebocyte proliferation and reduction
of sebaceous lipogenesis might the sebocyte-specific activity of isotretinoin and support a pro-
drug/drug relation between isotretinoin and tretinoin [162]. This data has been confirmed by
RNAseq analysis, which supported the pro-drug role of isotretinoin in acne [163]. Interestingly,
isotretinoin activates the PI3K/Akt pathway, decreases the nuclear content of FoxO1 and its
transcriptional activity in sebocytes and reduces the proliferation of IGF1- or insulin-stimulated
sebocytes in vivo and in vitro [67]. On the other hand, an anti-inflammatory effect has been
attributed to isotretinoin through a reduction of MMP in sebum [164] (Fig. 11) and normalization
of exaggerated TLR-2-mediated innate immune responses in acne patients [165]. Neutrophil
gelatinase-associated lipocalin, which is enhanced in acne-involved sebaceous glands [139]
mediates isotretinoin-induced apoptosis of human sebaceous gland cells [166].
The liver exhibits a tremendous capacity to store retinoids. Only huge and chronic daily ingestion
of more than 100,000 IU (33.3 times the recommended daily allowance) of vitamin A for at least 6
months or ingestion of at least 100 times the recommended daily allowance in a period of hours to
days is considered toxic [167]. Retinoid toxicity manifests as intense headaches, due to increased

intracranial pressure resulting from excess cerebrospinal fluid, termed ‘‘pseudotumor cerebrei,’’
dry skin and hair loss, bone, joint, and muscle pain, fatigue, anorexia and diplopia. In addition,
hypervitaminosis A has been reported to induce psychosis [168]. Positron emission tomography
Accepted Article
scans taken before and after four months of treatment revealed a decrease in orbitofrontal cortex
glucose metabolism following isotretinoin treatment [169]. Although some patients taking
isotretinoin reported headaches and subtle changes in irritability or mood, none of them were
found to be clinically depressed, as assessed by the Hamilton Depression Scale [169]. In animal
studies, norepinephrine tissue levels were increased under retinoid treatment suggesting that
retinoids may influence
norepinephrinergic transmission. In cultured brain cells, chronic – but not short-term - isotretinoin
treatment led to increased intracellular serotonin levels and elevated serotonin-1A receptor and
blocking serotonin reuptake transporter protein levels [170] indicating that
isotretinoin can alter serotonergic signaling by exerting nongenomic effects, such as increased
protein stability [168].
Although prospective clinical studies did not reveal evidence of isotretinoin-induced depression,
an isotretinoin-sparing regimen – i.e. starting with low-dose isotretinoin and slowly advancing by
titrating the daily dose upwards according to the individual patient’s need and side effects
threshold - may potentially lead to stable remission, prevent acne relapses in patients with mild-to-
moderate acne as well as lead to lower incidence of side effects and lower cumulative costs in
patients with severe acne [171,172] in addition to possibly prevent the above mentioned central
side effects. Otherwise, nothing has practically changed, including the treatment guidelines,
despite initially promising retinoid derivative developments [173,174].
PPARγ modulation
Reduction of sebocyte differentiation, which can be induced by environmental factors [102], leads
to upregulation of the Akt/mTOR pathway, the expression of lipogenic genes and mono-
unsaturated fatty acids synthesis, lipoxygenase activity and inflammatory cytokine production
maintained by normal insulin levels, mimicking acne conditions [44]. Lipid production in acne
sebaceous glands is higher than in healthy sebaceous glands, which suggests that PPARγ might
play a protective role against excessive lipid accumulation and inflammatory responses, which
makes this nuclear receptor a possible therapeutic target in acne [44,76]. Indeed, azelaic acid was

shown to modulate the inflammatory response in human keratinocytes through PPARγ activation
[175]. The induction of sebocyte differentiation by PPARγ modulators normalizes the response to
insulin. In vivo treatment of 21 acne patients with the topical PPARγ modulator N-Acetyl-GED-
Accepted Article
0507-34-LEVO (NAC-GED0507 1% gel) ameliorated acne manifestations and induced
endogenous PPARγ levels in sebum and epithelial membrane antigen expression, a marker of
normal sebaceous differentiation, as well as decreased mTOR activation and inflammatory
molecule serum levels, confirming the in vitro results [176]. A phase IIb clinical study with NAC-
GED0507 in different concentrations is just completed (2018-003307-19).
Androgens and follicular hypoxia

In addition to their hyperproliferative effect [177], androgens enhance sebaceous lipogenesis [44],
which together with the enhanced proliferation of ductal keratinocytes causes hypoxia/anoxia in
the follicular canal and overexpression of the hypoxia-inducible factor-1 alpha (HIF-1α) [178].
The latter regulates the levels of sterol regulatory element-binding protein-1 and perilipin 2
(PLIN2) in human sebocytes leading to intracellular accumulation of lipid droplets [49]. PLIN2 is
the major perilipin regulated during sebocyte differentiation and controls sebaceous lipid
accumulation in vitro and sebaceous gland size in vivo [47]. RNA-seq analysis of sebocyte genes
under hypoxia revealed 256 differentially regulated genes, including several lipid droplet-
associated genes and 93 inflammatory mediators, including tumor necrosis factor-α and IL6.
Sebocyte treatment with an HIF-1α stabilizer reduced inflammatory mediator expression and
sebaceous lipogenesis, implicating the normalization of the follicular hypoxia environment in
potential anti-acne treatment [178].
Phytocannabinoids and sebaceous glands

GPR119, a recently deorphanized receptor and promising antidiabetic drug target, which is
expressed in human sebocytes, is involved in the metabolism of the endocannabinoid-like
substance oleoylethanolamide (OEA) [179]. OEA promotes differentiation of human sebocytes
and switches the cells to a proinflammatory phenotype. GPR119 was found downregulated in
acne-involved sebaceous glands. Dysregulation of the OEA/GPR119 pathway might contribute to
the development of seborrhea and acne. On the other hand, targeting cannabinoid receptors with
stable, exogenous ligands, like phytocannabinoids, might represent another concept of anti-acne
treatment. (−)-cannabidiol (CBD), a non-psychotropic phytocannabinoid, in contrast to

endocannabinoids [97,98], exerted anti-inflammatory effects, suppressed increased sebaceous
lipogenesis and inhibited pathologically accelerated cell proliferation in sebaceous glands [100].
CBD seems to induce these effects not via activation of the cannabinoid receptor 2, a modulator of
Accepted Article
the lipogenic effect of endocannabinoids, as it would be expected, but by other mechanisms. The
anti-inflammatory effect of CBD might be induced by the activation of the A2A adenosine
receptor resulting in up-regulation of tribbles homolog 3 and consequent inhibition of the pro-
inflammatory p65 NF-κB pathway in the downstream signaling. The lipostatic and
antiproliferative CBD effects were mediated via weak transient receptor potential vanilloid 4
activation, associated with the inhibition of ERK1/2/MAPK pathway and downregulation of
nuclear receptor interacting protein 1 [99]. Altogether, CBD alleviates several factors of
inflammatory acne via newly reported mechanisms making the compound interesting for clinical
evaluation. A phase Ib clinical study with the topical synthetic cannabinoid BTX 1503 revealed an
excellent safety profile and a 47% average reduction in inflammatory lesions after four weeks of
treatment. A phase II clinical study was currently completed (NCT03573518). The primary
endpoint of reduction in inflammatory lesions did not achieve statistical significance, due to the
high response rate of the placebo (40.2% vs. 40.5% of BTX1503), an unexpected result that has,
however, been currently observed in several clinical studies targeting diseases of the
pilosebaceous unit. In contrast, BTX1503 induced an average non-inflammatory lesion reduction
of 34.99% compared to 19.08% of the placebo (p=0.007).
Melanocortins
Working on hypophsectomised rats many years ago, Thody [180] has detected that αMSH
increases preputial gland sebum secretion and skin sebaceous gland lipogenesis, especially wax
ester biosynthesis. Several years later Böhm et al. [93] confirmed the sebotropic activity of αMSH
on human sebocytes in vitro. Due to the parallel suppression of IL1β by αMSH [93] and KDPT
(Lys-D-Pro-Thr), a tripeptide αMSH derivative, in cultured human sebocytes [181], the
superpotent αMSH analogue afamelanotide (Nle(4)-D-Phe(7)-αMSH) administered
subcutaneously led to reduction of the total number as well as the number of inflammatory acne
lesions 56 days after the first injection in a preliminary clinical study with 3 patients [182]. On the
other hand, melanocortin-5 receptor (MC5R) is expressed in human and mouse sebaceous glands
and has been associated with sebocyte differentiation and sebum production [183] and his targeted
disruption gave rise to reduced sebum production in mice [184]. In two multi-center, double-blind,

vehicle controlled, phase II study with 431 and 364 acne patients, the dual MC1R/MC5R
antagonist JNJ 10229570 (NCT01326780) and the αMSH mimetic compound MTC896
(NCT02395549) were investigated a topical agents for 12 weeks, however the results of both
Accepted Article
studies have not been published.
Leukotriene inhibition
The rate of apoptotic mature sebocytes and, therefore, the sebum released in the follicular canal, is
dependent on proapoptotic caspase cascades, which can be markedly upregulated by AA, an ω6
proinflammatory free FA, which is a Δ6-fatty acid desaturase-2 (FADS2)-induced metabolite of
the essential ω6-free FA LA and precursor of leukotriene-B4 (LTB4) and 15-
hydroxyeicosatetraenoic acid [2,15,47] (Fig. 2). The latter metabolic pathways are regulated by the
enzymes 5-lipoxygenase/leukotriene-A4-hydrolase and 15-lipoxygenase, respectively [185,186].
AA induces LTB4 and IL-6 release and enhances lipid synthesis in cultured human sebocytes
[15,187]. LTB4 is also a natural PPAR ligand [188]. Therefore, inhibition of LTB4 synthesis
through 5-lipoxygenase down-regulation may provide an attractive target for control of
inflammatory processes in acne, as already shown in respective experimental and clinical studies
[188-190]. A phase II clinical study with systemic zileuton has been conducted several years ago
(NCT00098358). Although patients treated with zileuton showed a mean reduction in the total
number of lesions of 25.3, compared to a mean reduction of 16.4 lesions in the placebo group the
overall result was not significant (p=0.085). However, the results were significant in a subset of
patients with more severe acne (baseline inflammatory lesions ≥30). Patients treated with zileuton
(n=26) showed a mean decrease in inflammatory lesions of 41.6% compared to 26.2% in the
placebo group (n=24; p=0.025). No zileuton-treated patient discontinued the study. The compound
was well tolerated with no serious adverse events reported in patients.
Acne vaccination
A secretory Christie-Atkins-Munch-Petersen (CAMP) factor of P. acnes has been detected up-
regulated in anaerobic bacterial cultures [191]. Mutation of CAMP factor significantly diminishes
P. acnes colonization and inflammation in mice, demonstrating a probable essential role of CAMP
factor in the cytotoxicity of P. acnes. Vaccination of mice with CAMP factor considerably
reduced the growth of P. acnes and the production and release of the murine counterpart of human
IL8, MIP-2 [192]. The efficacy of CAMP factor antibodies in the neutralization of the acne

inflammatory response was validated in an ex vivo acne model. The P. acnes CAMP factor and
the proinflammatory cytokines IL1β and IL8 were expressed at higher levels in acne lesions than
those in nonlesional skin. Incubation of ex vivo acne explants with monoclonal antibodies to
Accepted Article
CAMP factor markedly attenuated the amounts of IL1β8 and IL8. For vaccination, an antibody
against cell wall-anchored sialidase of P. acnes has been constructed [191], since recombinant
sialidase was shown to increase P. acnes cytotoxicity and adhesion on sebocytes in vitro. The anti-
sialidase antibody was developed in mice immunized with sialidase and neutralized P. acnes
cytotoxicity and IL8 production in vitro as well as induced protective immunity to the mice
against P. acnes [193]. A vaccine of CAMP 2 factor antibodies, which decreased the inflammatory
response in mice [192], might, therefore, become a more promising anti-acne treatment. Since the
evident antinflammatory activity of CAMP 2 factor antibodies may directly affect sebaceous
lipogenesis as well as the release of sebaceous endocrine factors [123,124] thr planed clinical
studies are expected with great interest.
Other therapeutic agents and approaches

Several other therapeutic agents and approaches have currently been proposed for the treatment of
acne, such as lupeol, a pentacyclic triterpene [194] (NCT02152865), resveratrol, which exerts
growth inhibitory effects on human sebocytes in vitro through the inactivation of the PI3K/Akt
pathway [195] (NCT03563365), eupatilin, an O-methylated flavone which inhibits the IGF1-
induced lipogenesis and inflammation in human sebocytes in vitro [78], inhibitors of dipeptidyl
peptidase IV, such as Lys[Z(NO2)]-thiazolidide, Lys[Z(NO2)]-pyrrolidide, sitagliptin, and
aminopeptidase N, such as actinonin, bestatin [92], Chinese bayberry extract and its active
constituent myricetin which suppress P. acnes-stimulated proinflammatory cytokines in human
sebocytes in vitro [196]. Photodynamic treatment with δ-aminolevulinic acid [197,198], which
suppresses IL1β-mediated cytokine expression and signaling in human sebocytes based on the
fluorescence excited in the follicular canal [199,200] and is under investigation in clinical studies
(NCT00673933, NCT01689935, NCT01347879, NCT00594425 NCT00613444, NCT01245946).
The human sebaceous gland expresses numerous signaling pathways and receptors, which may
lead to disease development but also become appealing pharmaceutical targets [201]. Further
clinical trials against acne mostly concern topical agents that may act via sebosuppressive effects,
antimicrobial properties or anti-inflammatory actions. A topical formulation of olumacostat

glasaretil 5% gel did not meet the primary end points in two randomized, double-blind, vehicle
controlled, efficacy and safety phase 3 study of 744 patients with acne vulgaris (NCT03127956,
NCT03028363), despite the promising results of the phase IIa study with 108 patients [202]. A
Accepted Article
Phase 2, randomized, double-blind, vehicle-controlled, parallel group multicenter study to evaluate
the safety and efficacy of a topical formulation of the antibacterial peptide omiganan
pentahydrochloride on 320 patients with acne vulgaris has been completed in 2017 but no results
have been announced (NCT02571998). On the other hand, the antiandrogen cortexolone 17α-
propionate (clascoterone) has been investigated in two identical, multicenter, randomized, vehicle-
controlled, double-blind, phase 3 studies with 1440 patients with acne vulgaris and an open-label,
long-term extension study (NCT02720627, NCT02682264). Participants were randomized to
treatment with clascoterone 1% cream vs vehicle. At week 12, treatment success rates with
clascoterone cream were 18.4% vs 9.0% and 6.5% with vehicle, respectively (p<0.001). Both
inflammatory and non-inflammatory lesions were significantly reduced. Adverse events rates were
low and mostly mild; the predominant local skin reaction was trace or mild erythema [203]. In the
long-term study, 609 patients were enrolled. Overall, 110 (18.1%) patients experienced 191 side
effects with nasopharyngitis (n=20) been the most frequently reported one [204].
Phase 2 studies with systemic anti-acne drugs include finasteride (NCT02502669), biologics and
low dose antiinflammatory antibiotics were rather disappointing, not achieving or announcing any
results yet [205].
CONCLUSION
Endocrinological/metabolic and inflammatory/immunological aspects are correlated closely in the
aetiopathogenic (Fig. 1) and clinical (Fig. 12) initiation and development of acne. The simplified
“triangle” of acne pathogenesis is based on these two cardinal factors (Fig. 13) and it is reasonable
that the majority of future efforts for acne treatment take this concept into consideration (Fig.
14). Indeed, the unique programme of sebocyte terminal differentiation and death, the so called
holocrine secretion, is influenced by inflammatory and metabolic (lipid) signaling with common
denominator the selective regulation of PPAR subtypes. Autophagy provides substrates for energy
generation and biosynthesis of new cell structure proteins contributing to the normally increased
sebaceous gland metabolic functions, which are also regulated by extracellular calcium signaling,

essential lipids and hormones. The ultimate differentiation product of human sebocytes, sebum
also co-regulates the inflammatory sebocyte status. Sebum composition is controlled among others
by sexual hormones, neuropeptides, endogenous opioids and environmental agents, which may
Accepted Article
function as endocrine disruptors. Sebum changes might induce inflammation and initiate
underlying immune mechanisms leading to acne lesions. Current new therapeutic efforts on acne
concentrate on anti-inflammatory/immunologically active concepts, which are able to regulate
sebaceous lipogenesis. At last, current molecular studies based on published molecular datasets
confirmed the major role of inflammation in acne development [206,207]. Similar studies on
metabolic pathways are under investigation.

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66. W. J. Harrison, J. J. Bull, H. Seltmann, C. C. Zouboulis, M. P. Philpott, J. Invest. Dermatol.
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67. Y. Mirdamadi, A. Thielitz, A. Wiede, A. Goihl, C. C. Zouboulis, U. Bommhardt, S. Quist,
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74. E. Makrantonaki, K. Vogel, S. Fimmel, N. Oeff, H. Seltmann, C. C. Zouboulis, Exp.

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75. A. Dozsa, B. Dezso, B. I. Toth, A. Bacsi, S. Poliska, E. Camera, M. Picardo, C. C.
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76. A. Dozsa, J. Mihaly, B. Dezso, E. Csizmadia, T. Keresztessy, L. Marko, R. Rühl, E.
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77. M. Im, S. Y. Kim, K. C. Sohn, D. K. Choi, Y. Lee, Y. J. Seo, C. D. Kim, Y. L. Hwang, C. C.
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79. C. C. Zouboulis, Hormones 2004, 3, 9.
80. C. C. Zouboulis, W. Chen, M. J. Thornton, K. Qin, R. L. Rosenfield, Horm. Metab. Res.
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82. W. Chen, S.J. Tsai, H.-M. Sheu, J.-C. Tsai, C. C. Zouboulis, Exp. Dermatol. 2010, 19, 470.
83. A. T. Slominski, B. Zbytek, G. Nikolakis, P. Manna, C. Skobowiat, M. Zmijewski, W. Li, Z.
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91. U. Wollina, M. B. Abdel-Naser, R. Ganceviciene, C. C. Zouboulis, Dermatol. Clin. 2007,
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92. R. Ganceviciene, V. Graziene, S. Fimmel, C. C. Zouboulis, Br. J. Dermatol. 2009, 160, 345.
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93. M. Böhm, M. Schiller, S. Ständer, H. Seltmann, Z. Li, T. Brzoska, D. Metze, H. B. Schiöth,
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95. C. C. Zouboulis, H. Seltmann, N. Hiroi, W. Chen, M. Young, M. Oeff, W. A. Scherbaum, C.
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96. R. Ganceviciene, V. Graziene, M. Böhm, C. C. Zouboulis, Exp. Dermatol. 2007, 16, 547.
97. N. Zákány, A. Oláh, A. Markovics, E. Takács, A. Aranyász, S. Nicolussi, F. Piscitelli, M.
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99. A. Oláh, A. Markovics, J. Szabó-Papp, P. Szabó, C. Stott, C. C. Zouboulis, T. Bíró, Exp.
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100. A. Oláh, B. I. Tóth, I. Borbíró, K. Sugawara, A. G. Szöllősi, G. Czifra, B. Pál, L. Ambrus, J.
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101. Q. Ju, C. C. Zouboulis, Rev. Endocr. Metab. Disord. 2016, 17, 449.
102. Q. Ju, C. C. Zouboulis, Biosafety 2013, 2, 3.
103. Q. Ju, C. C. Zouboulis, L. Xia. Dermatoendocrinol. 2009, 1, 125.
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106. T. Hu, D. Wang, Q. Yu, L. Li, X. Mo, Z. Pan, C. C. Zouboulis, L. Peng, L. Xia, Q. Ju,
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107. X. X. Hou, G. Chen, A. M. Hossini, T. Hu, L. Wang, Z. Pan, L. Lu, K. Cao, Y. Ma, C. C.
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109. Q. Yu, T. Hu, X. Mo, C. Zhang, L. Xia, C. C. Zouboulis, Q. Ju, Chin. J. Dermatol. 2013, 46,

557.
110. J. H. Saurat, G. Kaya, N. Saxer-Sekulic, B. Pardo, M. Becker, L. Fontao, F. Mottu, P.
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124. C. C. Zouboulis, Dermatology 2001, 203, 277.

125. T. G. Tzellos, V. A. Zampeli, E. Makrantonaki, C. C. Zouboulis, Expert Opin.
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126. A. C. Jahns, B. Lundskog, R. Ganceviciene, R. H. Palmer, I. Golovleva, C. C. Zouboulis, A.
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131. G. J. Yoshida, H. Saya, C. C. Zouboulis, Biochem. Biophys. Res. Commun. 2013, 438, 640
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132. Q. Zhang, H. Seltmann, C. C. Zouboulis, J. B. Travers, Exp. Dermatol. 2006, 15, 769.
133. Q. Zhang, H. Seltmann, C.C. Zouboulis, R. L. Konger, J. Invest. Dermatol. 2006, 126, 42.
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136. Z. J. Li, D. K. Choi, K. C. Sohn, M. S. Seo, H. E. Lee, Y. Lee, Y. J. Seo, Y. H. Lee, G. Shi,
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138. G. Yang, S. H. Yeon, H. E. Lee, H. C. Kang, Y.-Y. Cho, H. S. Lee, C. C. Zouboulis, S.-H.
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140. M. Dahlhoff, T. Fröhlich, G. J. Arnold, C. C. Zouboulis, M. R. Schneider, Exp. Dermatol.
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141. M. Dahlhoff, C. C. Zouboulis, M. R. Schneider, J. Dermatol. Sci. 2016, 81, 124.
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143. D. Töröcsik, D. Kovács, E. Camera, M. Lovászi, K. Cseri, G. G. Nagy, R. Molinaro, R.
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145. K. Iinuma, T. Sato, N. Akimoto, N. Noguchi, M. Sasatsu, S. Nishijima, I. Kurokawa, A. Ito,
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146. I. Nagy, A. Pivarcsi, K. Kis, A. Koreck, L. Bodai, A. McDowell, H. Seltmann, S. Patrick, C.
C. Zouboulis, L. Kemény, Microbes Infect. 2006, 8, 2195.
147. C. H. Chen, Y. Wang, T. Nakatsuji, Y. T. Liu, C. C. Zouboulis, R. Gallo, L. Zhang, M. F.
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148. T. Nakatsuji, M. C. Kao, J.-Y. Fang, C. C. Zouboulis, L. Zhang, R. L. Gallo, C.-M. Huang,
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150. D-Y. Lee, K. Yamasaki, J. Rudsil, C. C. Zouboulis, G. T. Park, J.-M. Yang, R. L. Gallo, J.
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152. M. Lovászi, A. Szegedi, C. C. Zouboulis, D. Törőcsik, Dermatoendocrinol. 2017, 9,
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153. D. Törőcsik, D. Kovács, S. Póliska, Z. Szentkereszty-Kovács, M. Lovászi, A. Szegedi, C. C.
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154. C. C. Zouboulis, C. Beutler, H. F. Merk, J. M. Baron, Dermatoendocrinol. 2017, 9,
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155. R. Ganceviciene, C. C. Zouboulis, Expert Rev. Dermatol. 2007, 2, 693.
156. C. C. Zouboulis, V. Bettoli, Br. J. Dermatol. 2015, 172(suppl 1), 27.
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160. A. M. Nelson, K. L. Gilliland, Z. Cong, D. M. Thiboutot, J. Invest. Dermatol. 2006, 126,
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162. M. Tsukada, M. Schröder, T. C. Roos, R. A. S. Chandraratna, U. Reichert, H. F. Merk, C. E.
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163. D. Kovács, K. Hegyi, A. Szegedi, D. Deák, S. Póliska, R. Rühl, C. C. Zouboulis, D.
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164. E. Papakonstantinou, A. J. Aletras, E. Glass, P. Tsogas, A. Dionyssopoulos, J. Adjaye, S.
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175. A. Mastrofrancesco, N. Ottaviani, N. Aspite, G. Cardinali, E. Izzo, K. Graupe, C. C.
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176. M. Ottaviani, E. Flori, A. Mastrofrancesco, S. Briganti, V. Lora, B. Capitanio, C. C.
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178. K. O. Choi, M. Jinb, C. C. Zouboulis, Y. J. Lee, Dermatology 2020, [Online ahead of print].
179. A. Markovics, Á. Angyal, K. F. Tóth, D. Ádám, Z. Pénzes, J. Magi, Á Pór, I. Kovács, D.
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182. M. Böhm, J. Ehrchen, T. A. Luger, J. Eur. Acad. Dermatol. Venereol. 2014, 28, 108.
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192. Y. Wang, T. R. Hata, Y. L. Tong, M.-S. Kao, C. C. Zouboulis, R. L. Gallo, C.-M. Huang, J.
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195. J. Tuo, Q. Wang, C. C. Zouboulis, Y. Liu, Y. Ma, L. Ma, J. Ying, C. Zhang, L. Xiang,
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196. W. Liu, Q. Wang, J. Tuo, Y. Chang, J. Ying, M. Jiang, C. C. Zouboulis, L. Xiang,
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197. D. T. Xu, J. N. Yan, W. Liu, X. X. Hou, Y. Zheng, W. W. Jiang, Q. Ju, C. C. Zouboulis, X.
L. Wang, Dermatology 2018, 234, 43.
198. H. H. Kwon, J. Y. Yoon, S. Y. Park, S. Min, Y. I. Kim, J. Y. Park, Y. S. Lee, D. M.
Thiboutot, D. H. Suh, J. Invest. Dermatol. 2015, 135, 1491.

199. S. Y. Kim, M. Y. Hyun, K. C. Go, C. C. Zouboulis, B. J. Kim, Int. J. Mol. Med. 2015, 35,
1042.
200. E. O. Okoro, N. G. Bulus, C. C. Zouboulis, Dermatology 2016, 232, 156.
Accepted Article
201. V. A. Zampeli, T. Tzellos, E. Makrantonaki, C. C. Zouboulis, Curr. Pharm. Biotechnol.
2012, 13, 1898.
202. R. Bissonnette, Y. Poulin, J. Drew, H. Hofland, J. Tan, J. Am. Acad. Dermatol. 2017, 76, 33.
203. A. Hebert, D. Thiboutot, L. Stein Gold, M. Cartwright, M. Gerloni, E. Fragasso, A.
Mazzetti, JAMA. Dermatol. 2020, e200465..
204. L. Eichenfield, A. Hebert, L. Stein Gold, M. Cartwright, E. Fragasso, L. Moro, A. Mazzetti,
J. Am. Acad. Dermatol. 2020, [Online ahead of print].
205. C. C. Zouboulis, C. Dessinioti, F. Tsatsou, H. P. M. Gollnick, Exp. Opin. Investig. Drugs
2017, 26, 813.
206. B. Chen, Y. Zheng, Y. Liang, BioMed. Res. Int. 2019, 3739086.
207. X. Li, Y. Jia, S. Wang, T. Meng, M. Zhu, Dermatology 2019, [online ahead of print].

Table 1. Classification of endocrine-disrupting compounds according to their origin
Group Examples
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___________________________________________________________________________
Natural and artificial hormones Phytoestrogens, 3-omega fatty acids, contraceptives, thyroid
compounds
Drugs with hormonal side effects Naproxen, metoprolol, clofibrate
Industrial and household chemicals Cosmetics, phthalates, alkyl phenol ethoxylate detergents,
fire retardants, plasticizers, solvents, 1,4-dichloro-benzene,
polychlorated biphenyls, heavy metals (arsenic, cadmium,
lead, mercury)
Side products of industrial and
house hold processes Polycyclic aromatic hydrocarbons, dioxins,
pentachlorobenzene

Table 2. Isotretinoin effectiveness on human sebaceous gland cells and in acne
Cellular function Effect Cellular Molecular

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mechanism mechanism
Proliferation* Inhibition Intracellular RAR-mediated
isomerization in
tretinoin
Proliferation Reduction the Activation of the Decrease of FoxO1
proliferation of phosphoinositol-3- nuclear content
IGF1- or insulin- kinase/Akt pathway
stimulated sebocytes
Cell differentiation Inhibition CRABPII and Inhibition of
involucrion CRABPII and
reduction involucrin
transcription
Proliferation/Apoptosis* Inhibition/induction Cell cycle arrest Retinoid receptor-
independent
Apoptosis in acne Induction Reduction of Inhibition of
enhanced neutrophil lipocalin
gelatinase- transcription
associated lipocalin
Lipid synthesis* Reduction Inhibition of RAR- and RXR-
terminal mediated
differentiation
Lipid synthesis in acne Decreased androgen Decrease of Inhibition of 3α-
and lipid synthesis domains for steroid hydroxysteroid
metabolizing activity
enzymes and lipid of retinol
synthesis dehydrogenase and
downregulation of
lipid synthetizing

pathways
Inflammation in acne Reduction Inhibition of the Reduction of MMP,
migration of expression
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neutrophils
Innate immunity in acne Downregulation Normalization of Reduction of
exaggerated TLR2- S100A2, S100A7,
mediated innate S100A9 expression
immune response
Wound reconstruction Enhancement Collagen synthesis Upregulation of
in acne collagen and
fibronectin
* Sebocyte-specific
RAR, retinoic acid receptor; IGF1, insulin-like growth factor 1; CRABPII, cellular retinoic acid-
binding protein II; RXR, retinoid X receptor; MMP, metalloproteases; TLR2, Toll-like receptor 2

LEGENDS TO THE FIGURES
Fig. 1. Network of the four core events in acne formation. Acne development depends on
hyperseborrhoea, epithelial hyperproliferation, Propionibacterium acnes activity within the
Accepted Article
follicle, and inflammation. Androgens, ligands of peroxisome proliferator-activated receptors,
regulatory neuropeptides with hormonal and non-hormonal activity and environmental factors lead
to hyperseborrhoea, epithelial hyperproliferation in the ductus seboglandularis and acro-
infundibulum and the expression of pro-inflammatory chemokines and cytokines, which stimulate
the development of comedones and inflammatory lesions. IGF1, insulin-like growth factor 1;
mTORC1, mammalian target of rapamycin complex 1; PPARs, peroxisome proliferator-activated
receptors; SREBP1, sterol regulatory element-binding protein 1 (from: S. Moradi-Tuchayi, E.
Makrantonaki, R. Ganceviciene, C. Dessinioti, S. Feldman, C. C. Zouboulis, Nat. Rev. Dis.
Primers 2015, 1, 15029, with permission).
Fig. 2. Sebaceous lipogenesis is dependent on the fatty acids available. While saturated ω3 and
ω6 fatty acids are essential, ω9 can be synthetized by the sebaceous glands. The saturated /
unsaturated fatty acid ratio defines inflammatory triggering and can initiate comedogenesis (from:
C. C. Zouboulis, E. Jourdan, M. Picardo, J. Eur. Acad. Dermatol. Venereol. 2014, 28, 527, with
permission).
Fig. 3. Regulation of the biological function of human sebaceous gland cells. LXR: liver X
receptors, PPAR: peroxisome-proliferator activated receptors (from: E. Makrantonaki, R.
Ganceviciene, C. C. Zouboulis, Dermatoendocrinol. 2011, 3, 41, with permission).
Fig. 4. MALP-2 and Toll-like receptor pathway of innate immunity. BLP, bacterial lipoprotein
(MALP-2); LPS, lipopolysaccharides; LTA, lipoteichoic acid; TLR, Toll-like recptor; MD-2,
myeloid differentiation factor-2; IL, interleukin; NFκB, nuclear factor 'κ-light-chain-enhancer' of
activated B-cells; hBD2, human β-defensin 2; GM-CSF, granulocyte-macrophage colony-
stimulating factor; MMP, metalloptoteases; TNFα, tumor necrosis factor-α
Fig. 5. Initiation of inflammation in the pilosebaceous unit and development of
microcomedones. The initial IL-1β signal released by follicular keratinocytes and sebocytes leads
to IL8 secretion by sebocytes and additional enhancement of IL6 and TNFα signaling, leading to
attraction of professional inflammatory cells. IL, interleukin; TNF, tumor necrosis factor
(modified from: C. C. Zouboulis, Akt. Dermatol. 2006, 32, 296 and C. C. Zouboulis, Hautarzt
2013, 64, 235, under permission)

Fig. 6. Inflammatory events occurring during the initiation of acne lesions. a) normal
pilosebaceous unit, b) uninvolved skin of acne patient, c) small acne papule (microcomedone) less
than 6 h-old. Increasing perifollicular accumulation of T cells can be seen. Immunohistochemical
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staining carried out using a CD3 antibody and visualized by a standard streptavidin biotin
horseradish peroxidase technique. Scale bar: 100 mm (modified from: A. H. T. Jeremy, D. B.
Holland, S. G. Roberts, K. F. Thomson, W. J. Cunliffe, J. Invest. Dermatol. 2003, 121, 20, under
permission). d) Pilosebaceous unit in facial skin of acne patients. A faintly hypertrophic sebaceous
gland is observed. Dilated capillaries and perivascular lymphocytes (d and f) are early signs of
inflammatory process in acne-involved skin. Dilated plugged orifice of hair follicle - sign of acne
comedone (e) (from: E. Makrantonaki, R. Ganceviciene, C. C. Zouboulis, Dermatoendocrinol.
2011, 3, 41, under permission).
Fig. 7. Pathways of immunity. A) Innate immunity response: Epithelial cells, including sebocytes
can respond as non-professional inflammatory cells when challenged by bacteria or bacterial
antigens, B) Adaptive immunity response
Fig. 8. P. acnes-induced inflammation is sebaceous glands. (A) Wild-type (WT) and NLRP3-
deficient mice (NLRP3-/-) were injected intradermally with P. acnes (right ear) or an equal
volume of PBS (left ear). Inflammation-induced redness of the ear was visualized 24 h after
injection. (B) Hematoxylin and eosin (HE)-stained frozen tissue sections of the ear injected with
PBS alone, P. acnes in wild-type (WT) mice or P. acnes in NLRP3-/- mice. Bars=200 mm. The
lower panel of specimens were immunohistochemically stained with IL1β monoclonal antibodies.
Bars=50 mm. (C) Expression of IL1β in sebaceous glands of normal human facial skin and facial
inflammatory acne lesions in immunohistochemically stained paraffin-embedded skin specimens.
Bars=100 mm. (D) Left, immunofluorescence labeling of I1β (green) in human SZ95 sebocytes
after exposure to P. acnes at a multiplicity of infection (MOI) of 10 for 24 h. Nuclei were
counterstained with 4,6-diamidino-2-phenylindole
(blue). Bars=100 mm. Middle, quantitative reverse-transcriptase–PCR analysis of IL1β mRNA
expression after P. acnes stimulation (MOI of 1and 10). Right, IL1β secretion in supernatants at a
MOI after P. acnes stimulation assessed using ELISA. Data were analyzed by the Student’s t-test
(**p<0.01, ***p<0.001) and represent mean±SEM (modified from Z. J. Li, D. K. Choi, K. C.
Sohn, M. S. Seo, H. E. Lee, Y. Lee, Y. J. Seo, Y. H. Lee, G. Shi, C. C. Zouboulis, C. D. Kim, J.
M. Lee, M. Im, J. Invest. Dermatol. 2014, 134, 2747, under permission).
Fig. 9. Leptin, sebaceous lipogenesis and inflammation. Activation of the full-length

leptin receptor (Ob-Rb) with leptin in human SZ95 sebocytes results in upregulation of
the inflammatory enzymes cyclooxygenase (COX)2 and 5-lipooxygenase (LOX) and increased
expression and secretion of the inflammatory cytokines interleukin (IL)6 and IL8, which is likely
Accepted Article
to be further induced by the activation of the signal transducer and activator of
transcription (STAT)3 and nuclear factor NFκB pathways. Treatment with leptin also results in
altered lipogenesis by increasing the ratios of monounsaturated FA and
polyunsaturated fatty acids to saturated fatty acids. The enlargement of lipid droplets
on leptin treatment correlates with the increased levels of unsaturated free FA and triglycerides
(from D. Töröcsik, D. Kovács, E. Camera, M. Lovászi, K. Cseri, G. G. Nagy, R. Molinaro, R.
Rühk, G. Tax, K. Szabó, M. Picardo, L. Kemény, C. C. Zouboulis, E. Remenyik, Br. J. Dermatol.
2014, 171, 1326, under permission).
Fig. 10. Overview of the possible role of sebocytes in modulating macrophage activation,
differentiation and function. Sebocytes are able to contribute to the polarization of monocytes
towards alternative activation with the produced lipids, as marked by increased levels of CD206,
CD209 and FXIII-A expression, of which linoleic and oleic acids are essential. Furthermore,
linoleic and oleic acids contribute to an increased potential of macrophages to uptake P. acnes,
whereas palmitic, oleic and stearic acids augment the macrophage response to bacteria. IL1β,
interleukin-1β; TNFα, tumour necrosis factor-α (from: M. Lovászi, M. Mattii, K. Eyerich, A.
Gacsi, E. Csanyi, D. Kovacs, R. Ruhl, A. Szegedi, L. Kemeny, M. Stahle, C. C. Zouboulis, S.
Eyerich, D. Töröcsik, Br. J. Dermatol. 2017, 177, 1671, under permission).
Fig. 11. Metalloproteases are reduced in sebum of facial acne lesions under treatment with
isotretinoin. (left) Representative gelatin zymography of metalloproteases in sebum aliquots
during systemic per os (lanes 4–6) and topical (lanes 7–9) treatment with isotretinoin. Arrows
indicate protein molecular weight markers (lane 1): phosphorylase b (97.4 kDa), bovine serum
albumin (66.2 kDa), L-glutamic dehydrogenase (55.0 kDa), and ovalbumin (42.7 kDa). Lane 2:
migration of purified promatrix metalloprotease (proMMP)-2 (72 kDa); lane 3: proMMP-9 (92
kDa); lanes 4 and 7: 0-day samples; lanes 5 and 8: 30-day samples; lanes 6 and 9: 60-days
samples. (right) Quantitative analysis of metalloprotease activity in sebum following systemic per
os or topical treatment of acne patients with isotretinoin. Bars represent the mean±SD. * p<0.05;
*** p<0.01 as compared with 0-day samples (from: E. Papakonstantinou, A. J. Aletras, E. Glass,
P. Tsogas, A. Dionyssopoulos, J. Adjaye, S. Fimmel, P. Gouvousis, R. Herwig, H. Lehrach, C. C.
Zouboulis, G. Karakiulakis, J. Invest. Dermatol. 2005, 125, 673, with permission).

Fig. 12. Natural cycling of the sebaceous follicle and development of acne lesions.
Uncontrolled overstimulation of the liposebaceous unit by hormones (like in puberty by
androgens) or defect negative feedback regulation (enhancement of inflammatory signaling) lead
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to the development of clinically detectable acne lesions, such as comedones and inflammatory
papules (modified from: C. C. Zouboulis, A. Eady, M. Philpott, L. A. Goldsmith, C. Orfanos, W.
J. Cunliffe, R. Rosenfield, Exp. Dermatol. 2005, 14, 143, under permission).
Fig.13. “Triangle” of acne pathogenesis. Simplified model of the major mutually active factors
leading to the development of acne lesions (from: C. C. Zouboulis, Akt. Dermatol. 2006, 32, 296
and C. C. Zouboulis, Hautarzt 2013, 64, 235, under permission).
Fig. 14. Pathophysiological processes involved in acne vulgaris and therapeutic targets. The
pathogenesis of acne involves several processes including sebocyte differentiation and sebum
production as well as inflammation and immunological reaction. These processes are regulated by
circulating sex hormone levels as well as locally synthesized hormones,
neuropeptides, the microbiota and pro-inflammatory cytokines, lipid mediators,
antimicrobial peptides and monounsaturated fatty acids (MUFAs), which represent possible
therapeutic targets. α-MSH, α-melanocyte-stimulating hormone; CRH, corticotropin-releasing
hormone; DHEA, dehydroepiandrosterone; EGFR, epidermal growth factor receptor; IGF1,
insulin-like growth factor 1; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NF-κB,
nuclear factor-κB; PPARγ, peroxisome proliferator-activated receptor-γ; TNF, tumour necrosis
factor; VIP, vascular intestinal polypeptide (modified from: S. Moradi-Tuchayi, E. Makrantonaki,
R. Ganceviciene, C. Dessinioti, S. Feldman, C. C. Zouboulis, Nat. Rev. Dis. Primers 2015, 1,
15029, with permission).

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Endocrinology and immunology of acne: Two sides of the same coin

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Corresponding author: Prof. Dr. Christos C. Zouboulis, Departments of Dermatology,

Keywords: Acne, Sebaceous gland, Inflammation

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SEBOCYTE DIFFERENTIATION, HOLOCRINE SECRETION AND LIPOGENESIS

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CALCIUM SIGNALING AND SEBOCYTE DIFFERENTIATION

SEBUM AND ACNE

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HORMONES AND ACNE

Insulin-like growth factor-1 is involved in the development of acne

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Genetic variation of steroid hormones and acne

Neurohormones and acne

Innervation of the human sebaceous gland is yet to be conclusively confirmed. Numerous

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Endogenous opioids and cannabinoids in acne

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FOLLICULAR DIFFERENTIATION AND ACNE

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P. ACNES, SEBACEOUS LIPOGENESIS, INFLAMMATION AND THE UNDERLYING

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At last, sebocytes participate in skin inflammation by recruiting and communicating with

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NEW ASPECTS OF ACNE TREATMENT

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Androgens and follicular hypoxia

Phytocannabinoids and sebaceous glands

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Other therapeutic agents and approaches

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Cellular function Effect Cellular Molecular

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