期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 141, 期 5, 页码 1677-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2017.12.1002
关键词
Atopic dermatitis; pruritogens; brain-derived natriuretic peptide; pruritus; skin; dorsal root ganglion; keratinocytes; dendritic cells; soluble N-ethylmaleimide-sensitive factor activating protein receptors
资金
- Science Foundation Ireland [15/SIRG/3508T, 13/CDA/2093]
- Hamad Medical Corporation, Qatar
Background: T(H)2 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 beta 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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