TRPM8 activation attenuates inflammatory responses in mouse models of colitis

Authors

Rithwik Ramachandran, University of Calgary
Eric Hyun, University of Calgary
Liena Zhao, University of Calgary
Tamia K. Lapointe, University of Calgary
Kevin Chapman, University of Calgary
Christina L. Hirot, University of Calgary
Subrata Ghosh, University of Calgary
David D. McKemy, University of Southern California
Nathalie Vergnolle, University of Calgary
Paul L. Beck, University of Calgary
Christophe Altier, University of Calgary
Morley D. Hollenberg, University of Calgary

Document Type

Article

Publication Date

4-30-2013

Journal

Proceedings of the National Academy of Sciences of the United States of America

Volume

110

Issue

18

First Page

7476

Last Page

7481

URL with Digital Object Identifier

10.1073/pnas.1217431110

Abstract

Transient Receptor Potential Melastatin-8 (TRPM8), a recently identified member of the transient receptor potential (TRP) family of ion channels, is activated by mild cooling and by chemical compounds such as the supercooling agent, icilin. Since cooling, possibly involving TRPM8 stimulation, diminishes injury-induced peripheral inflammation, we hypothesized that TRPM8 activation may also attenuate systemic inflammation. We thus studied the involvement of TRPM8 in regulating colonic inflammation using twomousemodels of chemically induced colitis. TRPM8 expression, localized immunohistochemically in transgenic TRPM8GFP mouse colon, was up-regulated in both human- and murine-inflamed colon samples, as measured by real-time PCR. Wild-type mice (but not TRPM8-nulls) treated systemically with the TRPM8 agonist, icilin showed an attenuation of chemically induced colitis, as reflected by a decrease in macroscopic and microscopic damage scores, bowel thickness, and myeloperoxidase activity compared with untreated animals. Furthermore, icilin treatment reduced the 2,4,6-trinitrobenzenesulfonic acid-induced increase in levels of inflammatory cytokines and chemokines in the colon. In comparison with wild-type mice, Dextran Sodium Sulfate (DSS)-treated TRPM8 knockout mice showed elevated colonic levels of the in flammatory neuropeptide calcitonin-gene-related peptide, although inflammatory indices were equivalent for both groups. Further, TRPM8 activation by icilin blocked capsaicin-triggered calcitonin-gene-related peptide release fromcolon tissue ex vivo and blocked capsaicin-triggered calcium signaling in Transient Receptor Potential Vaniloid-1 (TRPV1) and TRPM8 transfected HEK cells. Our data document an anti-inflammatory role for TRPM8 activation, in part due to an inhibiton of neuropeptide release, pointing to a novel therapeutic target for colitis and other inflammatory diseases.