de Jong P R, Takahashi N, Peiris M, Bertin S, Lee J, Gareau M G, Paniagua A, Harris A R, Herdman D S, Corr M, Blackshaw L A, Raz E
1] Department of Medicine, University of California, La Jolla, California, USA [2] University Medical Center Utrecht, Utrecht, Utrecht, The Netherlands.
1] Department of Medicine, University of California, La Jolla, California, USA [2] Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Mucosal Immunol. 2015 May;8(3):491-504. doi: 10.1038/mi.2014.82. Epub 2014 Oct 1.
TRPM8 is the molecular sensor for cold; however, the physiological role of TRPM8+ neurons at mucosal surfaces is unclear. Here we evaluated the distribution and peptidergic properties of TRPM8+ fibers in naive and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8(-/-) mice were hypersusceptible to dextran sodium sulfate (DSS)-induced colitis, and that Trpm8(-/-) CD11c+ DCs (dendritic cells) showed hyperinflammatory responses to toll-like receptor (TLR) stimulation. This was phenocopied in calcitonin gene-related peptide (CGRP) receptor-deficient mice, but not in substance P receptor-deficient mice, suggesting a functional link between TRPM8 and CGRP. The DSS phenotype of CGRP receptor-deficient mice could be adoptively transferred to wild-type (WT) mice, suggesting that CGRP suppresses the colitogenic activity of bone marrow-derived cells. TRPM8+ mucosal fibers expressed CGRP in human and mouse colon. Furthermore, neuronal CGRP contents were increased in colons from naive and DSS-treated Trpm8(-/-) mice, suggesting deficient CGRP release in the absence of TRPM8 triggering. Finally, treatment of Trpm8(-/-) mice with CGRP reversed their hyperinflammatory phenotype. These results suggest that TRPM8 signaling in mucosal sensory neurons is indispensable for the regulation of innate inflammatory responses via the neuropeptide CGRP.
瞬时受体电位阳离子通道亚家族M成员8（TRPM8）是冷觉分子传感器；然而，TRPM8阳性神经元在黏膜表面的生理作用尚不清楚。在此，我们评估了TRPM8阳性纤维在未受刺激和发炎结肠中的分布及肽能特性，以及它们在黏膜炎症中的作用。我们发现，Trpm8基因敲除小鼠对葡聚糖硫酸钠（DSS）诱导的结肠炎高度敏感，且Trpm8基因敲除的CD11c阳性树突状细胞（DCs）对Toll样受体（TLR）刺激表现出过度炎症反应。降钙素基因相关肽（CGRP）受体缺陷小鼠出现类似表现，但P物质受体缺陷小鼠未出现，这表明TRPM8与CGRP之间存在功能联系。CGRP受体缺陷小鼠的DSS表型可通过过继转移至野生型（WT）小鼠，这表明CGRP可抑制骨髓来源细胞的致结肠炎活性。在人和小鼠结肠中，TRPM8阳性黏膜纤维表达CGRP。此外，在未受刺激和经DSS处理的Trpm8基因敲除小鼠的结肠中，神经元CGRP含量增加，这表明在缺乏TRPM8触发的情况下，CGRP释放不足。最后，用CGRP治疗Trpm8基因敲除小鼠可逆转其过度炎症表型。这些结果表明，黏膜感觉神经元中的TRPM8信号传导对于通过神经肽CGRP调节先天性炎症反应必不可少。
