New mechanism underlying IL-31–induced atopic dermatitis - 04/05/18
, Masaki Moriyama, PhD c, Micha Feld, PhD d, Joerg Buddenkotte, MD, PhD e, f, Timo Buhl, MD g, Attila Szöllösi, PhD b, Jingming Zhang, PhD h, Paul Miller, PhD h, Andre Ghetti, PhD h, Michael Fischer, MD i, Peter W. Reeh, MD j, Chunxu Shan, PhD a, b, Jiafu Wang, PhD a, Martin Steinhoff, MD, PhD b, c, e, f, ⁎ 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 numéro
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