TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP.
TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP.
复制标题
作者：
TRPM 8是冷的分子传感器;然而，TRPM 8+神经元在粘膜表面的生理作用尚不清楚。在这里，我们评估了TRPM 8+纤维在幼稚和炎症结肠中的分布和肽能特性，以及它们在粘膜炎症中的作用。我们发现Trpm 8 −/−小鼠对DSS诱导的结肠炎易感，Trpm 8 −/− CD 11 c + DCs对TLR刺激表现出高度炎症反应。这在CGRP受体缺陷的小鼠中表现出表型，但在P物质受体缺陷的小鼠中没有，表明TRPM 8和CGRP之间存在功能联系。CGRP受体缺陷小鼠的DSS表型可以过继转移到WT小鼠，表明CGRP抑制骨髓来源的细胞的大肠杆菌活性。TRPM 8+粘膜纤维在人和小鼠结肠中表达CGRP。此外，在未经处理和DSS处理的Trpm 8 −/−小鼠的结肠中，神经元CGRP含量增加，表明在没有TRPM 8触发的情况下，CGRP释放不足。最后，用CGRP治疗Trpm 8 −/−小鼠逆转了它们的过度炎症表型。这些结果表明，粘膜感觉神经元中的TRPM 8信号传导对于通过神经肽CGRP调节先天性炎症反应是必不可少的。
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 naïve and inflamed colons, as well as their role in mucosal inflammation. We found that Trpm8−/− mice were hypersusceptible to DSS-induced colitis, and that Trpm8−/− CD11c+ DCs showed hyperinflammatory responses to TLR stimulation. This was phenocopied in CGRP receptor deficient, 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 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 naïve 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.
登录
查看更多内容
影响因子：
15.9
作者：
de Jong, Petrus R.;Takahashi, Naoki;Raz, Eyal
通讯作者：
Raz, Eyal
影响因子：
3.6
作者：
Denda, Mitsuhiro;Tsutsumi, Moe;Denda, Sumiko
通讯作者：
Denda, Sumiko
DOI：
10.1073/pnas.0708469104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Abe, Kazumichi;Nguyen, Kim Phung;Raz, Eyal
通讯作者：
Raz, Eyal
影响因子：
7.4
作者：
Harrington, Andrea M.;Hughes, Patrick A.;Brierley, Stuart M.
通讯作者：
Brierley, Stuart M.
影响因子：
1.3
作者：
Garza, Armandina;Weinstock, Joel;Robinson, Prerna
通讯作者：
Robinson, Prerna