title: TRPM8 on mucosal sensory nerves regulates colitogenic responses by innate immune cells via CGRP.
abstract: 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.
authors.affiliation: 1] Department of Medicine, University of California, La Jolla, California, USA [2] University Medical Center Utrecht, Utrecht, Utrecht, The Netherlands.
authors.forename: P R
authors.initials: PR
authors.lastname: de Jong
authors.affiliation: 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.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Peiris
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bertin
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Gareau
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Paniagua
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Harris
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Herdman
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Corr
authors.affiliation: Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
authors.forename: L A
authors.initials: LA
authors.lastname: Blackshaw
authors.affiliation: Department of Medicine, University of California, La Jolla, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Raz
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011984:Sensory Receptor Cells / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D018040:Receptors, Neurokinin-1; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D016264:Dextran Sulfate; D015740:Calcitonin Gene-Related Peptide