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Sensory nerves mediate spontaneous behaviors in addition to inflammation in a murine model of psoriasis

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Xenia Kodji, Kate L. Arkless, Zizheng Kee, Simon J Cleary, Aisah A Aubdool, Elizabeth Evans, Paul Caton, Simon C Pitchford, Susan D Brain

Original languageEnglish
Pages (from-to)1578-1594
JournalFASEB Journal
Volume33
Issue number2
Early online date11 Sep 2018
DOIs
Accepted/In press30 Jul 2018
E-pub ahead of print11 Sep 2018
PublishedFeb 2019

King's Authors

Abstract

Psoriasis is characterized by keratinocyte hyperproliferation, erythema, as well as a form of pruritus, involving cutaneous discomfort. There is evidence from both clinical and murine models of psoriasis that chemical or surgical depletion of small-diameter sensory nerves/nociceptors benefits the condition, but the mechanisms are unclear. Hence, we aimed to understand the involvement of sensory nerve mediators using a murine model of psoriasis and associated spontaneous behaviors, indicative of cutaneous discomfort. We have established an Aldara™ model of psoriasis in mice and chemically depleted the small diameter nociceptors in a selective manner. The spontaneous behaviors, in addition to the erythema and skin pathology, were markedly improved. Attenuated inflammation was associated with reduced dermal macrophage influx and production of reactive oxygen/nitrogen species (peroxynitrite and protein nitrosylation). Subsequently, this directly influenced observed behavioral responses. However, the blockade of common sensory neurogenic mechanisms for TRPV1, TRPA1, and neuropeptides (substance P and CGRP) using genetic and pharmacological approaches inhibited the behaviors, but not the inflammation. Thus a critical role of the established sensory TRP-neuropeptide pathway in influencing cutaneous discomfort is revealed, indicating the therapeutic potential of agents that block this pathway. The ongoing inflammation is mediated by a distinct sensory pathway involving macrophage activation.

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