Stress & Mast Cell Activation

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From initiating allergic immune responses to protecting against pathogenic threats, mast
cells play an important role in the immune system. However, hyperactive mast cells and the
sustained release of their associated inflammatory cytokines and mediators such as
interleukin (IL)-6 and histamine impact multiple body systems and may cause impaired
health. Identifying the triggers and contributors to mast cell dysregulation is an important
approach when assessing chronic inflammation and a patient’s clinical presentation.

Chronic psychological stress is one lifestyle component that may lower the threshold for
mast cell reactivity.1,2 Hormones involved in the stress response such as corticotropin-
releasing hormone (CRH) and cortisol are closely linked to mast cell activation and
degranulation. Mast cells and associated stress hormones have been implicated in skin
diseases such as psoriasis and chronic urticaria3-5 and continue to be studied for their
potential role in gastrointestinal disorders6,7 and neuroinflammation.8,9

A systems biology perspective may be most effective to address the complexity of

multisystem inflammation that involves dysregulated mast cells. In regard to chronic stress
exposure, lifestyle approaches, including mind-body therapies, may help to attenuate the
stress response, downregulate the inflammatory cascade, and calm mast cell reactivity. What
mindfulness-based practices may align with your patient’s treatment strategy and health
goals?

Skin, Stress, & Mast Cell Activation

Compiled research suggests that the skin responds to psychological stress through the
complex interactions of skin-based immune cells, hormones, and neurotransmitters.3,4 Under
stress, keratinocytes and mast cells have been found to increase secretion of the
inflammatory cytokine IL-6 and stress-related mediators such as cortisol and corticotropin-
releasing hormone (CRH).3 Specific to urticaria pathology, skin mast cells activated by CRH
contribute to vasodilation and increased vascular permeability,4 and stress may amplify these
conditions. A 2020 systematic review of human in vivo and ex vivo studies reported that
while further investigation into underlying causal factors is warranted, a significant
association exists between chronic urticaria, mast cell mediators (i.e., histamine),
neuroimmune inflammation, and stress exposure.4

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Psoriasis is a chronic autoimmune skin disease. While stress has previously been
highlighted as a risk factor for autoimmune conditions,10 research investigations continue to
detail the mechanisms and the role of mast cells in the psychological stress-psoriasis
relationship.11 Most recently, studies indicate that skin mast cells near psoriatic plaques
express receptors for the stress hormone CRH, which may increase CRH-induced mast cell
secretion of inflammatory cytokines such as IL-6.5 The secreted IL-6 may then contribute to
psoriatic lesion pathogenesis and further hypothalamic-pituitary-adrenal (HPA) axis
dysregulation.5

Stress & Mast Cells: A Gut-Brain Perspective

Mast cell mediators have been implicated in gastrointestinal disorders and neurological
conditions such as irritable bowel syndrome (IBS)12 and migraine.13 While exact pathogenic
pathways and mechanisms are not yet clarified, human studies and animal models continue
to illustrate the impact of psychological stress on mast cells operating within the gut-brain
axis.6,8,9,14 A 2022 study that used a mouse model of eosinophilic enteritis found that
psychological stress exposure worsened small intestine inflammation, increased intestinal
permeability, and significantly increased both the intestinal mRNA expression of CRH and
the number of mast cells compared to controls.7 A 2020 clinical study (n=21 patients with
irritable bowel syndrome with diarrhea [IBS-D] and 17 healthy controls) investigated the role
of CRH, also called corticotropin-releasing factor, on IBS mucosal function.6 Intestinal
responses were evaluated in subjects after receiving 5-mL saline solution (placebo) and
CRH (100 µg), and researchers reported the following results:6

Compared to healthy subjects, base measurements of mast cell–associated and

affected proteins (tryptase and albumin) were higher in patients with IBS-D.
Albumin output increased for patients with IBS-D after CRH exposure.
Tryptase release, a marker for mast cell activation, increased significantly for both
groups after CRH exposure.
Abdominal pain worsened only in patients with IBS-D after CRH exposure.

Research also continues to investigate suggested neuroimmune connections between

stress-mediated mast cell activation and the pathogenesis of neurological diseases. CRH
activation of mast cells, potential disruption of the blood-brain barrier, intestinal permeability,
and neuroinflammation are some of the components recently evaluated in this complex,
multisystem relationship.8,9

Lifestyle Approaches: The Mind-Body Connection

Stress is a common trigger for a wide range of mast cell activation symptoms.2 An older
survey conducted by the Mastocytosis Society in 2014 found that among 366 members of
the US-based advocacy, research, and education organization for patients with mast cell–
related disorders, 81% identified stress as a trigger for their mast cell–related symptoms.15

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While research studies clarify the critical mechanisms and pathways involved in stress-mast
cell interactions, mind-body and stress transformation therapies may benefit mast cell
dysregulation and symptomology.1,16,17

A 2022 systematic review of 40 studies (n=3,112 patients) evaluated the efficacy of

psychological therapies and mind-body practices in the management of dermatologic
diseases, primarily psoriasis and atopic dermatitis.18 Investigators found that the most
promising practices were cognitive behavioral therapy, mindfulness-based interventions, and
habit reversal therapy.18 A 2022 systematic review specifically evaluated meditation as an
adjunctive treatment for psoriasis symptoms, severity, and patient quality of life.19 Of the six
randomized controlled trials included in the review, five showed reduced disease severity
after eight to twelve weeks of guided meditation and one measured positive mental health
benefits in psoriasis patients.19 Beyond the skin, mind-body practices such as mindfulness-
based cognitive therapy have also shown benefit for reducing symptoms and improving
quality of life in patients with IBS.20

In addition to disease-specific benefits, studies indicate that mind-body practices such as

yoga, meditation, tai chi, and mindfulness help to improve overall levels of stress-related
hormones21 and inflammatory cytokines.22,23 As an example, a 2022 randomized controlled
trial (n=281) evaluated the benefits of integrative-body-mind-spirit (IBMS) and Qigong
interventions for patients with both depressive symptoms and reported sleep disturbance.24
After eight weekly interventions, compared with controls, IBMS and Qigong were effective for
relieving depression symptoms and reducing both sleep disturbances and levels of the
inflammatory cytokines IL-6 and IL-1-beta.24

Mind-body therapies may help reduce stress, regulate mast cell hyperactivity, and improve a
range of health-related symptoms. Identifying sources of chronic stress and incorporating
stress transformation practices that best suit a patient’s lifestyle and preference is part of the
functional medicine approach to improved health and wellness. The IFM Toolkit provides
easy and accessible resources to personalize lifestyle-based therapies and includes
Strategies for Transforming Stress. This toolkit item suggests a range of stress-relief
practices, from community support, spiritual practice, and laughter to journaling, practicing
gratitude, and meditation. Learn more about lifestyle-based interventions and the functional
medicine approach to immune health and resilience at IFM’s upcoming Immune Advanced
Practice Module (APM).

References

1. Hamilton MJ. Nonclonal mast cell activation syndrome: a growing body of

evidence. Immunol Allergy Clin North Am. 2018;38(3):469-481.
doi:1016/j.iac.2018.04.002

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 2. Jennings SV, Slee VM, Zack RM, et al. Patient perceptions in mast cell
disorders. Immunol Allergy Clin North Am. 2018;38(3):505-525.
doi:1016/j.iac.2018.04.006
3. Pondeljak N, Lugovic-Mihic L. Stress-induced interaction of skin immune cells,
hormones, and neurotransmitters. Clin Ther. 2020;42(5):757-770.
doi:1016/j.clinthera.2020.03.008
4. Konstantinou GN, Konstantinou GN. Psychological stress and chronic urticaria: a
neuro-immuno-cutaneous crosstalk. a systematic review of the existing evidence. Clin
Ther. 2020;42(5):771-782. doi:1016/j.clinthera.2020.03.010
5. Marek-Jozefowicz L, Czajkowski R, Borkowska A, et al. The brain-skin axis in
psoriasis-psychological, psychiatric, hormonal, and dermatological aspects. Int J Mol
Sci. 2022;23(2):669. doi:3390/ijms23020669
6. Guilarte M, Vicario M, Martínez C, et al. Peripheral corticotropin-releasing factor
triggers jejunal mast cell activation and abdominal pain in patients with diarrhea-
predominant irritable bowel syndrome. Am J Gastroenterol. 2020;115(12):2047-2059.
doi:14309/ajg.0000000000000789
7. Kanamori A, Tanaka F, Ominami M, et al. Psychological stress exacerbates
inflammation of the ileum via the corticotropin-releasing hormone-mast cell axis in a
mouse model of eosinophilic enteritis. Int J Mol Sci. 2022;23(15):8538.
doi:3390/ijms23158538
8. Kempuraj D, Mentor S, Thangavel R, et al. Mast cells in stress, pain, blood-brain
barrier, neuroinflammation and Alzheimer’s disease. Front Cell Neurosci. 2019;13:54.
doi:3389/fncel.2019.00054
9. Bhuiyan P, Wang YW, Sha HH, Dong HQ, Qian YN. Neuroimmune connections
between corticotropin-releasing hormone and mast cells: novel strategies for the
treatment of neurodegenerative diseases. Neural Regen Res. 2021;16(11):2184-2197.
doi:4103/1673-5374.310608
10. Song H, Fang F, Tomasson G, et al. Association of stress-related disorders with
subsequent autoimmune disease. JAMA. 2018;319(23):2388-2400.
doi:1001/jama.2018.7028
11. Wozniak E, Owczarczyk-Saczonek A, Placek W. Psychological stress, mast cells, and
psoriasis—is there any relationship?. Int J Mol Sci. 2021;22(24):13252.
doi:3390/ijms222413252
12. Kurin M, Elangovan A, Alikhan MM, et al. Irritable bowel syndrome is strongly
associated with the primary and idiopathic mast cell disorders. Neurogastroenterol
Motil. 2022;34(5):e14265. doi:1111/nmo.14265
13. Conti P, D’Ovidio C, Conti C, et al. Progression in migraine: role of mast cells and pro-
inflammatory and anti-inflammatory cytokines. Eur J Pharmacol. 2019;844:87-94.
doi:1016/j.ejphar.2018.12.004
14. Hagiwara SI, Kaushal E, Paruthiyil S, Pasricha PJ, Hasdemir B, Bhargava A. Gastric
corticotropin-releasing factor influences mast cell infiltration in a rat model of functional
dyspepsia. PLoS One. 2018;13(9):e0203704. doi:1371/journal.pone.0203704

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 15. Jennings S, Russell N, Jennings B, et al. The Mastocytosis Society survey on mast
cell disorders: patient experiences and perceptions. J Allergy Clin Immunol Pract.
2014;2(1):70-76. doi:1016/j.jaip.2013.09.004
16. Golpanian RS, Kim HS, Yosipovitch G. Effects of stress on itch. Clin Ther.
2020;42(5):745-756. doi:1016/j.clinthera.2020.01.025
17. Graubard R, Perez-Sanchez A, Katta R. Stress and skin: an overview of mind body
therapies as a treatment strategy in dermatology. Dermatol Pract Concept.
2021;11(4):e2021091. doi:5826/dpc.1104a91
18. Rafidi B, Kondapi K, Beestrum M, Basra S, Lio P. Psychological therapies and mind-
body techniques in the management of dermatologic diseases: a systematic review.
Am J Clin Dermatol. 2022;23(6):755-773. doi:1007/s40257-022-00714-y
19. Bartholomew E, Chung M, Yeroushalmi S, Hakimi M, Bhutani T, Liao W. Mindfulness
and meditation for psoriasis: a systematic review. Dermatol Ther (Heidelb).
2022;12(10):2273-2283. doi:1007/s13555-022-00802-1
20. Henrich JF, Gjelsvik B, Surawy C, Evans E, Martin M. A randomized clinical trial of
mindfulness-based cognitive therapy for women with irritable bowel syndrome—effects
and mechanisms. J Consult Clin Psychol. 2020;88(4):295-310. doi:1037/ccp0000483
21. Moraes LJ, Miranda MB, Loures LF, Mainieri AG, Mármora CHC. A systematic review
of psychoneuroimmunology-based interventions. Psychol Health Med. 2018;23(6):635-
652. doi:1080/13548506.2017.1417607
22. Ng TKS, Fam J, Feng L, et al. Mindfulness improves inflammatory biomarker levels in
older adults with mild cognitive impairment: a randomized controlled trial. Transl
Psychiatry. 2020;10(1):21. doi:1038/s41398-020-0696-y
23. Nugent NR, Brick L, Armey MF, Tyrka AR, Ridout KK, Uebelacker LA. Benefits of yoga
on IL-6: findings from a randomized controlled trial of yoga for depression. Behav Med.
2021;47(1):21-30. doi:1080/08964289.2019.1604489
24. Ng SM, Yin MXC, Chan JSM, et al. Impact of mind-body intervention on
proinflammatory cytokines interleukin 6 and 1β: a three-arm randomized controlled trial
for persons with sleep disturbance and depression. Brain Behav Immun. 2022;99:166-
176. doi:1016/j.bbi.2021.09.022

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