| Autor: |
de Jong PR; 1] Department of Medicine, University of California, La Jolla, California, USA [2] University Medical Center Utrecht, Utrecht, Utrecht, The Netherlands., Takahashi N; 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., Peiris M; Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK., Bertin S; Department of Medicine, University of California, La Jolla, California, USA., Lee J; Department of Medicine, University of California, La Jolla, California, USA., Gareau MG; Department of Medicine, University of California, La Jolla, California, USA., Paniagua A; Department of Medicine, University of California, La Jolla, California, USA., Harris AR; Department of Medicine, University of California, La Jolla, California, USA., Herdman DS; Department of Medicine, University of California, La Jolla, California, USA., Corr M; Department of Medicine, University of California, La Jolla, California, USA., Blackshaw LA; Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK., Raz E; Department of Medicine, University of California, La Jolla, California, USA. |
| Abstrakt: |
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. |
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