0271-0749/02/2202-0103/0Journal of Clinical Psychopharmacology Copyright 2002 by Lippincott Williams & Wilkins, Inc.
Mast Cells and Stress—A Psychoneuroimmunological

Tufts University School of Medicine, Boston, Massachusetts The complexity of interactions among neurotransmit- well known for their involvement in allergic and ana- ters and neuromodulators in the brain continues to ex- phylactic reactions20; then, surface bound immunoglobu- pand. The involvement of immune molecules has added lin E (IgE) complexes with specific antigen, causing de- a new dimension. An important new contributor that is of granulation, like a foil package of popcorn popping until interest to psychopharmacology is a unique cell, named the contents overflow.21 Many of these molecules are pre- “mast cell” by Paul Erlich in 1887 because its numerous formed and stored in almost 500 secretory granules, metachromatic granules reminded him of a “well-fed while others are made do novo during or following stim- cell” (German ϭ Mastzellen).1 These cells are particularly ulation.22,23 It is fascinating that one cell should have such active in atopic individuals, who also have higher inci- plethora and diversity of potent molecules that include dences of affective disorders.2–5 Moreover, the allergy arachidonic acid products, biogenic amines, chemoat- season has been shown to affect mood and cognitive tractants, cytokines, growth factors, neuropeptides, pro- function in these patients.6 Stress is known to exacerbate teoglycans, and proteolytic enzymes (Table 2). Although many neuroinflammatory conditions7, but, until recently, the mast cell is ubiquitous in the body—including the mast cells were not suspected of being involved in con- brain, which does not suffer from allergic reactions be- ditions such as dermatoses8, irritable bowel syndrome9, cause IgE does not cross the blood-brain barrier—de- interstitial cystitis10, migraines11, and multiple sclerosis granulation occurs only in about 10% or so of atopic indi- (MS).12 Although Hans Seyle wrote the first definitive viduals. Moreover, increasing evidence indicates that work on stress13 and one on mast cells14, he did not link some molecules are released from mast cells without de- the two at that time. The effect of acute stress is particu- granulation, a process termed “differential release” and larly evident in systemic mastocytosis, a rare condition first reported for serotonin.24 Other biogenic amines25, characterized by abnormal proliferation and activation of arachidonic acid products26, and cytokines27 may also be mast cells.15,16 For these patients, and possibly many oth- released differentially. The morphological appearance of ers who have a neuroinflammatory syndrome with an af- this process is characterized by a more subtle set of fective component worsened by stress (Table 1), when changes within the electron dense content of the secre- anxiety rises, they know there will be a flare-up in symp- tory granules28 and has been called “piece-meal degranu- toms, which may include flushing of the skin, intestinal lation”29 or “intergranular activation”.30 The type(s) of upset, palpitations, migraines, and changes in mood and molecule(s) released may vary from person to person, cognitive function.12 These latter symptoms could be due and/or from organ to organ, depending on hormonal and to activation of brain mast cells, which are plentiful in the psychological state and the specific trigger.
Anatomical and functional associations have been re- Mast cells are found in most parts of the body and are ported between mast cells and neurons.31,32 Scanningelectron microscopy has documented mast cells close to Address requests for reprints to: Theoharis C. Theoharides, PhD, endothelial cells and to neuronal processes.33 Molecules MD, Department of Pharmacology and Experimental Therapeutics, released from nerves34–36, such substance P (SP), neu- Internal Medicine, Biochemistry, and Psychiatry Tufts University rotensin (NT), nerve growth factor (NGF), and opioids37 School of Medicine, New England Medical Center, Boston, Massa-chusetts. Address e-mail to: [email protected] could trigger mast cells (Table 3), from which histamine J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 TABLE 1. Neuroinflammatory syndromes with an affective could stimulate neuronal depolarization38, which could lead to further activation of mast cells. Moreover, mast cell derived chondroitin sulfate or heparin complexes with NGF and extends its half-life from a few minutes to many hours.39,40 Therefore, mast cell activation could lead to abnormal nerve proliferation (i.e., in neurofibro- matosis I).41 Intracranial mast cells could also be acti- vated by stimulation of the trigeminal42, sympathetic43, or sphenopalatine44 nerves and by acute restraint stress45, in the absence of any allergic diathesis. Some molecules from these mast cells could have direct ef-fects on the brain, while others could make the blood-brain barrier “leaky” and permit circulating chemicalsto enter the brain.46,47 Breakdown of the blood-brain bar-rier has been shown to precede any clinical or radi- Epinephrine, dopamine, phenylalanine (not synthesized, but taken Vasodilation, angiogenesis, mitogenesis, pain Tissue damage, pain, angiotensin II synthesis Cartilage synthesis, antiinflammatory, NGF stabilization Connective tissue synthesis, NGF stabilization Inflammation, leukocyte proliferation/activation Inflammation, vascular adhesion molecule expression Platelet activation & serotonin release CSF, colony stimulating factor; INF␥, interferon-␥; MIF, macrophage inflammatory factor; b-FGF, fibroblast growth factor; NGF, nerve growth factor; TGF-␤, transforming growth factor-␤; TNF-␣, tumor necrosis factor-␣; SRIF, somatostatin; GM-CSF, granulcyte monocyte-colony stimu-lating factor.
J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 TABLE 3. Triggers of mast cell activation quent release of histamine60 and IL-6.61 This action ofhistamine is not blocked by the usual antihistamines and appears to be mediated through the type 3 hista- mine receptor.62 IL-6, a key inflammatory cytokine63, is known be released from the hearts of patients with acute coronary syndrome, and is now considered a crit- Detergents; food additives; xenoestrogens ical player in coronary artery disease.64 Stress-induced Contrast media used in radiologyCytokines cardiac mast cell activation may be involved in unstable angina and myocardial infarction triggered by acute stress.65–67 Acute stress also results in bladder68 and in- Local anesthetics; neuromuscular junction blockers, opioids testinal69,70 mast cell activation, which may explain why symptoms in interstitial cystitis (IC) and irritable bowel Nerve growth factor, NGF; stem cell factor, SCF syndrome (IBS) patients worsen under stress.
Corticotropin-releasing hormone or factor (CRH or Adrenocorticotropic hormone, ACTH; corticotropin releasing CRF) is the first molecule released under stress and ac- hormone, CRH; estradiol; parathormone, PTH; urocortin, Ucn tivates the hypothalamic-pituitary-adrenal (PHA) axis.71 We have shown that CRH72 and structurally related uro- Bradykinin; calcitonin gene related peptide, CGRP; myelin basic cortin73 are powerful triggers of mast cell activation in protein, MBP; neurotensin, NT; somatostatin, SRIF; substance the skin. In fact, urocortin was 10 times more potent P, SP; vasoactive intestinal peptide, VIP than CRH and much more potent than SP.73 These actions were mimicked by acute stress74 and may be responsible for stress-induced alopecia areata.75 Such findings and the presence of both CRH and CRH recep- tors in the skin76 have led to the hypothesis that the skin has the equivalent of a local “pituitary-adrenal axis”.77 Recent findings showed that hypothalamic mast cell ac- tivation by chemical78 or immunologic means79 trig- Bacterial (Clostridium difficile); insect (fire ants); jelly fish (man gered activation of the HPA axis. This action could be mediated either through activation of CRH neurons di- rectly or the release of IL-6, a CRH independent activa- tor of the HPA axis.80 CRH or urocortin then could befurther released from recruited immune cells.81 Recognizing the involvement of mast cells and regulat- ing their secretion may be more important than simply ad- ographic signs of MS.48 Therefore, it is of interest that dressing the effects of individual mediators. A case in chemical49 or stress-induced stimulation of brain mast point is the clinical report (Pehlivanidis and associates, cells50 increased blood-brain barrier permeability. More- page 221 in this issue) of a young boy mistakenly diag- over, experimental allergic encephalomyelitis could not nosed and unsuccessfully treated for epilepsy. When it be induced in mast cell deficient mice.51 These findings was recognized that his seizures were induced by acute support the possible relationship between intracranial stress and were associated with his mastocytosis, he was mast cells and migraines52, as well as MS53, that are often successfully treated with a combination of the anxiolytic precipitated or worsened by stress.54–57 Dura mast cells antihistamine hydroxyzine and the tricyclic doxepin. The also express estrogen receptors33, a finding that, along efficacy of these compounds may be explained by the fact with the report that estrogen augments mast cell secre- that mast cell activation can be inhibited by certain tri- tion58, may possibly explain the higher incidence of mi- cyclic anxiolytic medications, such as amitriptyline and graines in women or their frequent occurrence during hydroxyzine82, and benzodiazepines.83 In fact, mast cells have been reported to express high affinity benzodi- Many patients also experience tachycardia and ar- azepine receptors.84,85 Hydroxyzine was recently shown to rhythmias related to stress. Such cardiovascular symp- inhibit neurogenic inflammation and experimental aller- toms may be associated with increased sympathetic ac- gic encephalomyelitis in rats.86 In humans, hydroxyzine tivity or reflex tachycardia in response to histamine- has been used successfully to treat acute pain87 and re- induced hypotension. However, such symptoms may mitting-relapsing MS.88 Such anxiolytic molecules could also be explained by the recent finding that acute stress be combined with naturally occurring flavonoids89 or pro- triggers mast cell activation in the heart59, with subse- teoglycans90 for more efficient inhibition of mast cell J CLIN PSYCHOPHARMACOL, VOL 22/NO 2, APRIL 2002 activation. Behavioral modification for stress reduction tem. Part I. Morphology, distribution and histochemistry. J Neu- also contributed to the treatment of the child described in 19. Pang X, Letourneau R, Rozniecki JJ, Wang L, Theoharides TC. De- the case report by Pehlivanidis and associates. We used finitive characterization of rat hypothalamic mast cells. Neuro- this approach because of our finding that training in re- laxation led to a sharp decline in the frequency and sever- 20. Galli SJ. New concepts about the mast cell. N Engl J Med 1993; ity of migraines and the release of the mast cell marker 21. Douglas WW. Involvement of calcium in exocytosis and the exocytosis-vesiculation sequence. Biochem Soc Symp 1974;39:1–28.
The mast cell has been considered an immune gate to 22. Schwartz LB. Mediators of human mast cells and human mast cell subsets. Ann Allergy 1987;58:226–35.
the brain91, as well as a sensor of environmental and 23. Serafin WE, Austen KF. Mediators of immediate hypersensitivity emotional stress.92 It has also been linked to many neu- reactions. N Engl J Med 1987;317:30–4.
ropathological processes.93–95 This versatile role of mast 24. Theoharides TC, Bondy PK, Tsakalos ND, Askenase PW. Differ- ential release of serotonin and histamine from mast cells. Nature cells96 compels a more appropriate name to indicate its polydimensional potential, perhaps “pleiotropocyte” 25. Dvorak AM, Macglashan DW, Jr., Morgan ES, Lichtenstein LM.
Vesicular transport of histamine in stimulated human basophils.
Blood 1996;88:4090–101.
26. Benyon R, Robinson C, Church MK. Differential release of hista- Acknowledgments
mine and eicosanoids from human skin mast cells activated byIgE-dependent and non-immunological stimuli. Br J Pharmacol Aspects of the work discussed were supported by the National Mul- tiple Sclerosis Society, the NIH, as well as by Kos Pharmaceuticals 27. Gagari E, Tsai M, Lantz CS, Fox LG, Galli SJ. Differential release (Miami, FL) and Theta Biomedical Consulting and Development Co.
of mast cell interleukin-6 via c-kit. Blood 1997;89:2654–63.
(Brookline, MA). Thanks are due to Mr. Barry Silverstein for continu- 28. Kops SK, Theoharides TC, Cronin CT, Kashgarian MG, Askenase ous encouragement and to Miss. Yahsin Tien for her patience and PW. Ultrastructural characteristics of rat peritoneal mast cells un-dergoing differential release of serotonin without histamine and without degranulation. Cell Tissue Res 1990;262:415–24.
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