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New mechanism underlying IL-31-induced atopic dermatitis

Meng J, Moriyama M, Feld M, Buddenkotte J, Buhl T, Szollosi A, Zhang J, Miller P, Ghetti A, Fischer M, Reeh P, Shan C, Wang J, Steinhoff M (2018)

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Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 141

Pages Range: 1677-1689.e8

Journal Issue: 5

DOI: 10.1016/j.jaci.2017.12.1002

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.

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APA:

Meng, J., Moriyama, M., Feld, M., Buddenkotte, J., Buhl, T., Szollosi, A.,... Steinhoff, M. (2018). New mechanism underlying IL-31-induced atopic dermatitis. Journal of Allergy and Clinical Immunology, 141(5), 1677-1689.e8. https://doi.org/10.1016/j.jaci.2017.12.1002

MLA:

Meng, Jianghui, et al. "New mechanism underlying IL-31-induced atopic dermatitis." Journal of Allergy and Clinical Immunology 141.5 (2018): 1677-1689.e8.

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