Immediate‐type allergic and protease‐mediated reactions are involved in scratching behaviour induced by topical application of Dermatophagoides farinae extract in NC/Nga mice

Abstract

Atopic dermatitis (AD)-like dermatitis can be induced by repeated topical application of an ointment containing Dermatophagoides farinae body (Dfb) extract in NC/Nga mice. This AD-like murine model also exhibits a biphasic increase in the number of scratching behaviour after topical application of Dfb ointment. In this study, we investigated the possible mechanisms underlying the scratching behaviour in each phase. An increase in the content of mast cell-derived mediators such as histamine and 5-hydroxytryptamine in the lesional skin and increased vascular permeability were observed in the early phase after the Dfb ointment application. Chlorpheniramine (H receptor antagonist) and cromoglycate (mast cell stabilizer) reduced the scratching behaviour in the early phase but not that in the later phase. Furthermore, the content of various endogenous pruritogens such as interleukin-31 and thymic stromal lymphopoietin in the lesional skin was increased 1 or 24 hours after the Dfb ointment application. Elevated expression of proteinase-activated receptor-2 (PAR-2) was also observed in the epidermis. Finally, gabexate (serine protease inhibitor) reduced the scratching behaviour in both phases, and anti-PAR2 antibody also showed a tendency to reduce both scratching behaviours. These findings suggest that immediate-type allergic reactions caused by mast cell degranulation and PAR-2 activation by proteases are involved in the scratching behaviour in this AD-like model.

Interaction of peripheral nerves and mast cells, eosinophils, and basophils in the development of pruritus

“…PAR‐2 is co‐expressed with CGRP and substance P in dorsal root ganglion (DRG) neurons. PAR‐2‐mediated release of neuronal CGRP and substance P subsequently generates pruritus and might enhance the additional mast cell activation, forming a self‐sustaining cycle of chronic pruritus Crosstalk between mast cells and peripheral neurons via PAR2 is a well‐established, and histamine‐independent mechanism that causes chronic pruritus in human and murine AD…”

Schwann cells as underestimated, major players in human skin physiology and pathology

“…The use of mouse lines to label and conditionally disrupt genes in SCs can then be adapted to the established mouse models of psoriasis and AD. [ ] Given the findings that global p75NTR KO alters the cutaneous inflammatory response, SC‐specific deletion of p75NTR (eg Plp‐CreER T2 p75NTR lox/lox ) should be done to validate the role of SC p75NTR signalling in these disease models. Finally, mouse lines that allow conditional disruption of SC activation are already existing (eg Plp‐CreER T2 Sox10 lox/lox ).…”

Role of mast cells and basophils in pruritus

“…141 Proteinase Thus, mast cells and PAR 2 are involved in pruritus of AD patients, which is independent of histamine. 137,143,144 However, AD patients demonstrate an upregulation of tryptase, underlining a potential role for mast cell-driven PAR 2 -signaling in AD. 137 These results in humans have been confirmed in multiple pruritic mouse models.…”

“…The pruritic capability of tryptase has been known for a long time and might be mediated—at least in part—by activation of PAR‐expressing sensory neurons . Thus, mast cells and PAR 2 are involved in pruritus of AD patients, which is independent of histamine . However, AD patients demonstrate an upregulation of tryptase, underlining a potential role for mast cell‐driven PAR 2 ‐signaling in AD .…”