| Summary: | 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.
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