Dr Liliana Shalamanova

Learning Outcomes

To be able to
• define inflammation
• discuss the pathogenesis of obesity and the role of
inflammation and immune cells in the pathogenesis of
Insulin resistance
 Inflammation

▪ Protective response of the innate immune system to invading pathogens or tissue injury

▪ The inflammatory response involves immune cells, blood vessels and molecular
mediators (e.g. chemokines and cytokines)

▪ Can be local or systemic; acute or chronic

▪ Associated with 5 signs:

• Redness
• Swelling
• Heath
• Pain
• Loss of function
 Roles of inflammation

1. To recruit effector molecules and cells to the site of infection

2. To induce local blood clotting (trapping pathogens and preventing their spread)

3. To initiate tissue repair

Role of pro-inflammatory cytokines

IL-8
 Roles of mast cells and basophils in inflammation

Release of histamine: 23 different physiological functions

Inflammation-related effects:

• dilation of blood vessels → fall in blood pressure

• vascular permeability → edema

• chemotaxis of leukocytes
Cells and mediators involved in a local Acute
Inflammatory Response
 Inflammation, pro- and anti-inflammatory
cytokines

▪ TNF:
• activate macrophages and neutrophils → ↑ phagocytic activity and the
release of lytic enzymes in the interstitial space
• stimulates endothelial cell to initiate blood clotting in local small vessels to contain
the pathogens
▪ TNF, IL-1 and IL-6: initiate systemic and acute phase response

▪ TGFβ (anti-inflammatory cytokine):

• limits the inflammatory response by inhibiting the activation of monocyte-derived
phagocytes and lymphocytes
• promotes tissue repair: accumulation and proliferation of fibroblasts and
build up of extracellular matrix
 Systemic response to inflammation

Local inflammatory response can be accompanied by a systemic response due

to pro-inflammatory cytokines released at the site of infection

▪ induction of fever
▪ ↑ synthesis of ACTH and
hydrocortisone hormones
▪ ↑ production of leukocytes
▪ production of acute-phase
proteins by the liver
 Sepsis

Sepsis: a spread of an infection into the bloodstream

Accompanied by a dramatic increase of systemic TNFa levels due to a mass TNFa release by activated
tissue macrophages

Systemic effects of TNFa:

• ↑ vasodylation → ↓blood pressure
• ↑ vascular permeability → loss of plasma volume Septic shock
• triggers blood clotting in small vessels → often leads to multiple organ failure due to
decreased organ perfusion
 Chronic Inflammation

Persistent increased expression of inflammatory cytokines

Caused by:
• Pathogens resistant to the immune defences

• Persistent tissue damage (e.g. autoimmune

diseases, cancer, atherosclerosis, etc.)
 Consequences of Chronic Inflammation

Chronic inflammation induces:

• continuous accumulation and activation of macrophages Normal adult kidney

• fibrosis (scarring of tissues): accumulation of fibroblasts and

excessive deposition of extracellular matrix proteins (tissue
repair gone wrong)
End-stage renal failure
• granuloma: activated macrophages surrounded by activated http://www-medlib.med.utah.edu/WebPath/
RENAHTML/RENALIDX.html#1
lymphocytes (e.g. tuberculosis lesions, dental granuloma)

http://imaging.consult.com/login
 Obesity

• Abnormal and excessive accumulation of adipose tissue in the body

• 57.8% of the global adult population are estimated to be overweight or obese by

2030

• Component of the Metabolic Syndrome (MetS), which is defined as a cluster of

metabolic risk factors such as abdominal obesity, dyslipidemia (abnormal levels of
cholesterol and other lipids), hyperglycemia and insulin resistance (IR)

• MetS is characterized by a state of low-grade inflammation that is implicated in the

development of chronic diseases such as type 2 diabetes (T2D), non-alcoholic fatty
liver disease (NAFLD) and cardiovascular disease (CVD)
 The Adipose tissues
Adipose Tissue:
adipocytes, lymphocytes, macrophages, fibroblasts, endothelial cells, and extracellular matrix

Distribution of WAT
White Adipose Tissue (WAT):
• Subcutaneous AT (SAT): in regions in the upper and lower body
• Visceral AT (VAT): around organs - omental, mesenteric,
mediastinal and epicardial

Brown adipose tissue (BAT):

• "Classical" BAT: highly vascularized deposits between the
shoulder blades, kidneys, neck, supraclavicular area, and
along the spinal cord.
Kwok, K., Lam, K. & Xu, A. Heterogeneity of white adipose tissue: molecular
basis and clinical implications. Exp Mol Med 48, e215 (2016).
• Beige AT: dispersed throughout white adipose tissue. https://doi.org/10.1038/emm.2016.5

Recruitment and activation of beige adipocytes is induced by cold

stress (aka browning or beiging of WAT)
 Adipocytes
White Adipocytes:
• Variable size: 25-250 um
• Single lipid droplet
• Few peripheral mitochondria and low oxidative rate
• Store energy as triglycerides
• Protect organs from lipotoxicity

Brown Adipocytes:
• numerous smaller lipid droplets
• Higher number of iron-containing mitochondria
• More capillaries than WAT Kwok, K., Lam, K. & Xu, A. Heterogeneity of white adipose tissue:
molecular basis and clinical implications. Exp Mol Med 48, e215 (2016).
https://doi.org/10.1038/emm.2016.5

Beige AT: between WAT and BAT

 Functions of the Adipose tissues

• Storage of energy

• Regulation of body temperature (non-shivering

thermogenesis)

• Endocrine function: secretion of adipokines

(cytokines) and hormones by

➢ adipocytes: e.g. adiponectin, MCP-1, TNFa,

leptin (energy homeostasis), resistin,
chemerin, etc.

➢ adipose-resident immune cells and

endothelial cells: apelin, visfatin, PAI-1,
MCP-1, TNFα and IL-6, etc.
Luo, Liping, and Meilian Liu. "Adipose tissue in control of metabolism." Journal of
endocrinology 231.3 (2016): R77-R99.
 The adipose tissue in obesity
Excessive calorie intake →
→ ↑ Adipocyte hyperplasia (adipocyte numbers) and
hypertrophy (adipocyte size) →
→↑adipocyte hypoxia, dysregulation of fatty acid fluxes, ↑
chemokine secretion, ↑ adipocyte cell death, and the
recruitment of pro-inflammatory cells →
→ ↑ proinflammatory cytokine release →
→ ↑ serine phosphorylation of insulin receptor
substrate-1 (IRS-1) →
→local and systemic insulin resistance →
→ whole body glucose and fatty acid metabolic
dysregulation

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 Role of adipocyte hyperplasia in
obesity
Excessive calorie intake →
→ ↑ Adipocyte hyperplasia (adipocyte numbers) and
hypertrophy (adipocyte size) →…..

?Is hyperplasia damaging or beneficial? recruitment and differentiation of

adipose precursor cells

Hyperplasia: Potential compensatory accumulation of fat into

mature adipocytes
mechanism to counterbalance the fat mass
expansion

Longo, M et al. Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic

Complications. Int. J. Mol. Sci. 2019, 20, 2358.
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 Resident Adipose Immune cells in
health

• Adipose Tissue Macrophages (ATMs) secrete anti-inflammatory IL-10

• Dendritic cells: activated anti-inflammatory Wnt/β catenin and PPARγ pathways
• Eosinophils: secrete IL-4 and IL-13 regulating adipocyte beiging (e.g. thermoregulation)
• Mast cells: facilitate preadipocyte → adipocyte transition
• B-cells: secrete the anti-inflammatory IL-10
• Treg: anti-inflammatory. Promote development of the anti-inflammatory M2 macrophage
phenotype in adipose tissue
 Adipose cells in Obesity
Adipocytes in obesity:
Hypertrophy → hypoxia → ↑ Pro-inflamatory cytokines, e.g.
MCP-1, TNFa and IL-6

• Adipose Tissue Macrophages (ATMs): ↑ numbers by 40-50%;

↑ secretion of pro-inflammatory cytokines; accumulate around dead or dying adipocytes
• Neutrophils: ↑ number and activation; ↑ROS production
• Dendritic cells: suppression of the anti-inflammatory Wnt/β catenin and PPARγ pathways; ↑pro-
inflammatory Th17 responses
• Eosinophils: ↓ eosinophil numbers → increased obesity in mice
• Mast cells: degranulate and release proteases → impaired glucose handling of adipocytes; ↑ pro-
inflammatory cell infiltration
• B-cells: accumulation of mature, class-switched B cells with IgG antibodies detecting adipose self-
antigens
 Adipose cells in Health and Obesity

Lumeng CN. Adipose tissue macrophages: a piece of the PAI of metabolic

syndrome. Sci Transl Med. 2010 Feb 24;2(20):20ps7. doi:
10.1126/scitranslmed.3000850. PMID: 20371488.

Ghazarian et al (2015). Immunopathology of Adipose Tissue during Metabolic Syndrome. Turk

patoloji dergisi. 31 Suppl 1. 172-180. 10.5146/tjpath.2015.01323.
 The systemic effects of obesity

Modified from: http://foodexposed.co.za/wp-content/uploads/2015/05/inflobesity.gif

 Glucose homeostasis

https://pdb101.rcsb.org/global-health/diabetes-mellitus/managing/non-pharmacological
Insulin resistance in obesity

TNFa and IL-6 impair glucose uptake and

induces insulin resistance
 Symptoms of Insulin resistance

Early stage: no symptoms.

Later stage – ↑ blood sugar levels:
Lethargy
Hunger
Difficulty concentrating (brain fog)
Weight gain around the middle (visceral fat
tissue)
High blood pressure
High cholesterol levels
Progression and treatment of Insulin
resistance

High doses of steroids over prolonged

period of time
Chronic stress
Cushing’s disease
Polycystic Ovary Disease (PCOD)

Reversal of the effect of Insulin resistance:

• Physical activity
• Healthy balanced diet
• Lower calorie intake
• Weight loss (bariatric) surgery (last resort)
 Suggested reading

Punt et al: Kuby Immunology 8th Edition, Chapter 15

Luo, Liping, and Meilian Liu. "Adipose tissue in control of metabolism." Journal of endocrinology 231.3
(2016): R77-R99.

Khan S, Chan YT, Revelo XS, Winer DA. The Immune Landscape of Visceral Adipose Tissue During Obesity
and Aging. Front Endocrinol (Lausanne). 2020 May 15;11:267. doi: 10.3389/fendo.2020.00267. PMID:
32499756; PMCID: PMC7243349.

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