New mechanism underlying IL-31–induced atopic dermatitis - 04/05/18
Abstract |
Background |
TH2 cell–released IL-31 is a critical mediator in patients with 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 neuroimmune axis of the skin is unknown.
Objective |
We sought to investigate the function of BNP in the peripheral sensory system and skin in IL-31–induced itch and neuroepidermal communication in patients with AD.
Methods |
Ca2+ imaging, immunohistochemistry, quantitative real-time PCR, RNA sequencing, knockdown, cytokine/phosphokinase arrays, enzyme immune assay, and pharmacologic inhibition were performed to examine the cellular basis of the IL-31–stimulated, BNP-related itch signaling in dorsal root ganglionic neurons (DRGs) and skin cells, transgenic AD-like mouse models, and human skin of patients with AD and healthy subjects.
Results |
In human DRGs we confirmed expression and co-occurrence of oncostatin M receptor β subunit and IL-31 receptor A in a small subset of the neuronal population. Furthermore, IL-31 activated approximately 50% of endothelin-1–responsive neurons, and half of the latter also responded to histamine. In murine DRGs IL-31 upregulated Nppb and induced soluble N-ethylmaleimide–sensitive factor activating protein receptor–dependent BNP release. In Grhl3PAR2/+ mice house dust mite–induced severe AD-like dermatitis was associated with Nppb upregulation. Lesional IL-31 transgenic mice also exhibited increased Nppb transcripts in DRGs and the skin; accordingly, skin BNP receptor levels were increased. Importantly, expression of BNP and its receptor were increased in the skin of patients with AD. In human skin cells BNP stimulated a proinflammatory and itch-promoting phenotype.
Conclusion |
For the first time, our findings show that BNP is implicated in AD and that IL-31 regulates BNP in both DRGs and the 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 might be a novel therapeutic strategy for AD and pruritic conditions.
Le texte complet de cet article est disponible en PDF.Key words : Atopic dermatitis, pruritogens, brain-derived natriuretic peptide, pruritus, skin, dorsal root ganglion, keratinocytes, dendritic cells, soluble N-ethylmaleimide–sensitive factor activating protein receptors
Abbreviations used : AD, BNP, CGRP, DRG, ET-1, FPKM, GAPDH, GSK3, hDC, HDM, hDRG, H&E, hKC, IL-31RA, JNK, mDRG, MMP9, NeuN, NPR1, NPR2, OSMRβ, PGP9.5, RNA-Seq, shRNA, SNAP-25, SNARE, SP, TG, Tg, V1, V7, VAMP, WT
Plan
Science Foundation Ireland is thanked for funding this research through a Starting Investigator Award (to J.M.; grant no. 15/SIRG/3508T), a Principle Investigator Award (to M.S.) and a Career Development Award (13/CDA/2093 to J.W.). M.S. received Excellence seed funding from Hamad Medical Corporation, Qatar. |
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Disclosure of potential conflict of interest: J. Meng has received a grant from Science Foundation Ireland (15/SIRG/3508T). M. Moriyama has received a grant from the National Institutes of Health. J. Zhang, P. Miller, and A. Ghetti have received fees for service from UCD. J. Wang has received a grant from Science Foundation Ireland (13/CDA/2093). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 5
P. 1677 - mai 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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