Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice

Pavlović, Sanja; Daniltchenko, Maria; Tobin, Desmond J.; Hagen, Edward H.; Hunt, Stephen P.; Klapp, Burghard F.; Arck, Petra C.; Peters, Eva M.J.

doi:10.1038/sj.jid.5701079

Cited by 135 publications

(169 citation statements)

References 102 publications

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“…Another study showed mast cells express the NK-1 receptor in both affected and unaffected psoriatic skin (6). NK-1 is also important in stress-induced murine skin mast cell activation (3,16), and in the development of atopic dermatitis in mice (68). In fact, stress increases SPpositive nerve fibers and mast cell contacts in mice (69), whereas an NK-1 receptor antagonist inhibits stress-induced mast cell degranulation in mice (72).…”

Section: Discussionmentioning

confidence: 99%

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IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Theoharides

Zhang²,

Kempuraj³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

272

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The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 μM) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL-33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component.inflammation | cytokines | IL-1 | innate immunity | stress

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Section: Discussionmentioning

confidence: 99%

“…Mast cells are often located close to SP-positive neuronal processes (66)(67)(68)(69). Mast cell-neuronal interactions might be involved in the pathophysiology of psoriasis and might participate in the exacerbation of symptoms by stress (7,13,70).…”

Section: Discussionmentioning

confidence: 99%

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Theoharides

Zhang²,

Kempuraj³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

295

272

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“…Both human and animal model studies demonstrated the importance of RBFOX1 in neuronal development and regulation (40,41). Although the connection between neurologic stimulation and atopic disease remains to be elucidated, it is noteworthy that stress can exacerbate atopic dermatitis via substance P-dependent neurogenic inflammation (42,43).…”

Section: Discussionmentioning

confidence: 99%

Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy

Fung

Glessner

et al. 2015

The Journal of Immunology

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Food allergy is a significant public health concern, especially among children. Previous candidate gene studies suggested a few susceptibility loci for food allergy, but no study investigated the contribution of copy number variations (CNVs) to food allergy on a genome-wide scale. To investigate the genetics of food allergy, we performed CNV assessment using high-resolution genome-wide single nucleotide polymorphism arrays. CNV calls from a total of 357 cases with confirmed food allergy and 3980 controls were analyzed within a discovery cohort, followed by a replication analysis composed of 167 cases and 1573 controls. We identified that CNVs in CTNNA3 were significantly associated with food allergy in both the discovery cohort and the replication cohort. Of particular interest, CTNNA3 CNVs hit exons or intron regions rich in histone marker H3K4Me1. CNVs in a second gene (RBFOX1) showed a significant association (p = 7.35 × 10−5) with food allergy at the genome-wide level in our meta-analysis of the European ancestry cohorts. The presence of these CNVs was confirmed by quantitative PCR. Furthermore, knockdown of CTNNA3 resulted in upregulation of CD63 and CD203c in mononuclear cells upon PMA stimulation, suggesting a role in sensitization to allergen. We uncovered at least two plausible genes harboring CNV loci that are enriched in pediatric patients with food allergies. The novel gene candidates discovered in this study by genome-wide CNV analysis are compelling drug and diagnostic targets for food allergy.

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“…The involvement of stress in cutaneous neurogenic inXammation and sensory nerve-mast cell interaction has been suggested in several studies [6,143]. Neuropeptides SP and VIP can eYciently activate human skin mast cells for rapid histamine release in situ [71] and in vitro [23].…”

Section: Interactions Between Mast Cells and Sensory Nerves In Psoriasismentioning

confidence: 99%

Is there a role for mast cells in psoriasis?

et al. 2008

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Mast cells have traditionally been considered as eVector cells in allergy but during the last decade it has been realized that mast cells are essentially involved in the mechanisms of innate and acquired immunity. Upon activation by anaphylactic, piecemeal degranulation or degranulation-independent mechanisms mast cells can secrete rapidly or slowly a number of soluble mediators, such as serine proteinases, histamine, lipid-derived mediators, cytokines, chemokines and growth factors. Mast cells can express cell surface co-stimulatory receptors and ligands, and they can express MHC class II molecules and thereby present antigens. These soluble factors and cell surface molecules can interact with other cells, such as endothelial cells, keratinocytes, sensory nerves, neutrophils, T cell subsets and antigen presenting cells which are essential eVectors in the development of skin inXammation. Besides promoting inXammation, mast cells may attempt in some circumstances to suppress the inXammation and epidermal growth but the regulation between suppressive and proinXammatory mechanisms is unclear. Psoriasis is characterized by epidermal hyperplasia and chronic inXammation where tryptase-and chymase-positive MC TC mast cells are activated early in the developing lesion and later the cells increase in number in the upper dermis with concomitant expression of cytokines and TNF superfamily ligands as well as increased contacts with neuropeptide-containing sensory nerves. Due to the intimate involvement of mast cells in immunity and chronic inXammation the role of mast cells in psoriasis is discussed in this review.

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Further Exploring the Brain–Skin Connection: Stress Worsens Dermatitis via Substance P-dependent Neurogenic Inflammation in Mice

Cited by 135 publications

References 102 publications

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

IL-33 augments substance P–induced VEGF secretion from human mast cells and is increased in psoriatic skin

Copy Number Variations in CTNNA3 and RBFOX1 Associate with Pediatric Food Allergy

Is there a role for mast cells in psoriasis?

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