TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP

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.