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
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 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).
Fight Inflammation and Stabilize Mast Cells Naturally
Innate Immunity: Diet and Lifestyle Support
Intestinal Permeability and Inflammatory Triggers
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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