New mechanism underlying IL-31-induced atopic dermatitis

Publication date: Available online 7 February 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Jianghui Meng, Masaki Moriyama, Micha Feld, Joerg Buddenkotte, Timo Buhl, Attila Szöllösi, Jingming Zhang, Paul Miller, Andre Ghetti, Michael Fischer, Peter W. Reeh, Chunxu Shan, Jiafu Wang, Martin Steinhoff
BackgroundT helper type 2 cell-released interleukin 31 (IL-31) is a critical mediator in atopic dermatitis (AD), a prevalent and debilitating chronic skin disorder. Brain-derived natriuretic peptide (BNP) has been described as a central itch mediator. The importance of BNP in peripheral (skin-derived) itch and its functional link to IL-31 within the neuro-immune axis of the skin is unknown.ObjectiveTo investigate the function of BNP in the peripheral sensory system and skin in IL-31-induced itch and neuro-epidermal communication in AD.MethodsCa²⁺-imaging, immunohistochemistry, quantitative real-time PCR, RNA-Seq, knockdown, cytokine/phosphor-kinase arrays, enzyme immune assay and pharmacological inhibition were subjected to examine the cellular basis of the IL-31-stimulated, BNP-related itch signaling in human DRG neurons (hDRG) and skin cells, transgenic AD-like mouse models, and human skin of AD and healthy subjects.ResultsIn hDRG, we confirmed expression and co-occurrence of OSMRβ and IL-31 receptor A in a small subset of neuronal population. Furthermore, IL-31 activated ∼50% of endothelin-1-responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced SNARE-dependent BNP release. In the Grhl3PAR2^/+mice, house dust mite-induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31Tg mice also exhibited increased Nppb transcripts in DRGs and skin; accordingly, skin BNP receptor was elevated. Importantly, expression of BNP and its receptor were increased in AD patient skin. In human skin cells, BNP stimulated a pro-inflammatory, itch-promoting phenotype.ConclusionOur findings show, for the first time, that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and skin. IL-31 enhances BNP release and synthesis, and orchestrates cytokine and chemokine release from skin cells, thereby coordinating the signaling pathways involved in itch. Inhibiting peripheral BNP function may be a novel therapeutic strategy for AD and pruritic conditions.



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