The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response
URL with Digital Object Identifier
© FASEB. The synthetic supercooling drug, icilin, and its primary receptor target, the cation channel transient receptor potential (TRP)melastatin-8 (TRPM8), have been described as potent negative regulators of inflammation in the colon.The aimof this study was to determinewhether the anti-inflammatory action of icilin could potentially be used to treat autoimmune neuroinflammatory disorders, such as multiple sclerosis (MS). During experimental autoimmune encephalomyelitis (EAE)-aCD4+T cell-driven murine model ofMS-we found that both wild-type (WT) andTRPM8-deficient EAEmicewereprotected fromdisease progression during icilin treatment, as evidenced by delays in clinical onset and reductions in neuroinflammation. In vitro, icilin potently inhibited the proliferation of murine and human CD4+ T cells, with the peripheral expansion of autoantigen-restricted T cells similarly diminished by the administration of icilin in mice. Attenuation of both TRPM8-/- and TRP ankyrin-1-/- T-cell proliferation by icilin was consistentwith theWTphenotype, which suggests a mechanism that is independent of these channels. Inaddition, icilin treatmentalteredthe expressional profile of activatedCD4+Tcells to one thatwas indicative of restricted effector function and limited neuroinflammatory potential. These findings identify a potent antiinflammatory role for icilin in lymphocyte-mediated neuroinflammation and highlight clear pleiotropic effects of the compoundbeyond classicTRPchannel activation.