Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.
Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.
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皮肤具有双重功能，既是身体和环境之间的屏障，也是感觉界面。为了防止病原体入侵，皮肤中含有特殊的免疫细胞，包括真皮树突状细胞(DDC)和产生白细胞介素17(IL-17)的γδT细胞(γδT17)，IL-23异常激活这些T细胞可引发银屑病样炎症。皮肤也受到周围神经网络的支配，这些神经网络由相对稀疏的自主神经和丰富的感觉纤维组成。已知自主神经系统和淋巴器官中的免疫细胞之间的相互作用有助于系统免疫，但周围神经如何调节皮肤免疫反应仍不清楚。在这里，我们将小鼠的皮肤暴露于咪喹莫特(Imquimod，ImQ)，它可以诱导依赖IL-23的牛皮癣样炎症。我们表明，表达离子通道TRPV1和NaV1.8的一部分感觉神经元对于驱动这种炎症反应是必不可少的。对完整皮肤的成像显示，大部分DDCS，IL-23的主要来源，与这些伤害性感受器密切接触。在选择性药物或遗传消融伤害性感受器后，DDCS不能在暴露于ImQ的皮肤中产生IL-23。因此，真皮γδT17细胞局部产生IL-23依赖的炎性细胞因子以及随后炎性细胞向皮肤募集的作用显著减少。皮内注射IL-23绕过了伤害性感受器与DDCS的联系，恢复了炎症反应。这些结果表明，TRPV1+NaV1.8+伤害性感受器通过与DDCS相互作用，调节IL-23/IL-17途径，控制皮肤免疫反应。
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 harbors specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17 producing γδ T cells (γδT17), whose aberrant activation by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibers. 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 unclear. Here, we have exposed the skin of mice to imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation. 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 nociceptors, DDCs failed to produce IL-23 in IMQ 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 dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. 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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影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
DOI：
10.1016/s0190-9622(99)70112-x
发表时间：
1999-09-01
影响因子：
13.8
作者：
Rapp, SR;Feldman, SR;Reboussin, DM
通讯作者：
Reboussin, DM
影响因子：
3.6
作者：
FARBER, EM;LANIGAN, SW;BOER, J
通讯作者：
BOER, J
影响因子：
25
作者：
Denise, A;Garcia, R;Sofroniew, MV
通讯作者：
Sofroniew, MV
DOI：
10.1126/science.1209985
发表时间：
2011-10-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Rosas-Ballina M;Olofsson PS;Ochani M;Valdés-Ferrer SI;Levine YA;Reardon C;Tusche MW;Pavlov VA;Andersson U;Chavan S;Mak TW;Tracey KJ
通讯作者：
Tracey KJ