Nature2014-06-17 1:49 PM

炎症中所涉及的周围神经元 Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation

论文摘要 

向小鼠皮肤上反复地局部施用抗病毒免疫调理剂“咪喹莫特”(IMQ),会激发与人类牛皮癣相似的由白介素-23介导的炎性病变。Ulrich H. von Andrian及同事发现,这种疾病模型中的皮肤炎症的产生取决于表达TRPV1 和Nav1.8离子通道的一个亚类的感觉神经元与皮肤内驻留的树状细胞之间的相互作用。与其他最近的研究工作联系起来,这一发现提出一个场景,在其中,有害痛觉纤维对环境信号进行整合,来调制针对各种不同感染性和促炎性刺激的局部免疫反应。

Abstract 

The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation1, 2, 3, 4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear5, 6. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation7, 8. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors9, 10, 11, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response12. These findings indicate that TRPV1+Nav1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

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