TRPM8 activation attenuates inflammatory responses in mouse models of colitis

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 two mouse models of chemically induced colitis. TRPM8 expression, localized immunohistochemically in transgenic TRPM8 GFP mouse colon, was up-regulated in both human-and murine-inflamed colon samples, as measured by realtime 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 inflammatory 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 from colon 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.

Menthoxypropanediol inhibits nerve growth factor‐induced nerve fibre sprouting in coculture models of sensory neurons and skin cells

“…1d). In accordance with our findings, Ramachandran et al observed a potent anti-inflammatory response with TRPM8 agonist icilin, but not with menthol (9). These findings indicate different mechanisms of cooling agents to modulate anti-inflammatory signalling that requires further investigation.…”

“…S5e). Ramachandran et al showed that TRPM8 agonist icilin inhibited pro-inflammatory CGRP release from distal colon tissue (9). As TRPM8 is coexpressed with TRPV1 in a subset of sensory neurons and suppresses TRPV1 activity [s13], we investigated whether MPD modulates the response to TRPV1 agonist capsaicin in sensory neurons.…”

“…Cooling agents, such as menthol or icilin, suppress itch by activating transient receptor potential ion channel M8 (TRPM8) on cutaneous Ad fibres (6,7) and have therefore been used as an antipruritic treatment for many years (8). Additionally, TRPM8 activation has recently been shown to attenuate inflammatory responses in a mouse model of colitis (9). A potential anti-inflammatory effect of cooling agents and its impact on itch-associated hyperinnervation in AD had not been studied.…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…This is in contrast to ;30-50% of acutely dissociated or cultured TRPM8-positive neurons that also functionally express TRPV1, suggesting species differences or artifacts related to neuronal isolation and culturing (Babes et al, 2004;Okazawa et al, 2004). Assessment of trpm8 2/2 mice and use of pharmacologic agents indicate that TRPM8 has diverse sensory roles and contributes to cold-induced allodynia and analgesia, pruritus, and inflammatory processes (Namer et al, 2008;Caspani et al, 2009;Su et al, 2011;Calvo et al, 2012;Lippoldt et al, 2013;Ramachandran et al, 2013;Shapovalov et al, 2013;Than et al, 2013). The use of selective antagonists have confirmed the involvement of TRPM8 in thermoregulation and augmented nerve excitability through voltagegated Na + channels (Gavva et al, 2012;Sarria et al, 2012).…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Among the 38 genomic loci, only two contain ion channel genes (KCNK5 23 and TRPM8 24 ). Hence, despite previous hypotheses of migraine as a potential channelopathy 5,25 , the loci identified to date do not support common variants in ion channel genes as strong susceptibility components in prevalent forms of migraine.…”