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

• Published in: Mucosal immunology Vol. 8; no. 3; pp. 491 - 504
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2015; Elsevier Limited
• Subjects: 631/250/2504/2506; 631/250/347; 631/250/371; 692/4020/1503/1581/1392/1388; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Calcitonin Gene-Related Peptide - deficiency; Calcitonin Gene-Related Peptide - genetics; Calcitonin Gene-Related Peptide - immunology; Colitis - chemically induced; Colitis - genetics; Colitis - immunology; Colitis - pathology; Colon - immunology; Colon - pathology; Dendritic Cells - immunology; Dendritic Cells - pathology; Dextran Sulfate; Epithelial Cells - immunology; Epithelial Cells - pathology; Female; Gastroenterology; Gene Expression Regulation; Humans; Immunity, Innate; Immunity, Mucosal; Immunology; Intestinal Mucosa - immunology; Intestinal Mucosa - pathology; Male; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Receptors, Neurokinin-1 - deficiency; Receptors, Neurokinin-1 - genetics; Receptors, Neurokinin-1 - immunology; Sensory Receptor Cells - immunology; Sensory Receptor Cells - pathology; Signal Transduction; TRPM Cation Channels - deficiency; TRPM Cation Channels - genetics; TRPM Cation Channels - immunology
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/mi.2014.82

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.