The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T‐cell response

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 aim of this study was to determine whether 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)—a CD4+ T cell-driven murine model of MS—we found that both wild-type (WT) and TRPM8-deficient EAE mice were protected from disease 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 consistent with the WT phenotype, which suggests a mechanism that is independent of these channels. In addition, icilin treatment altered the expressional profile of activated CD4+ T cells to one that was 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 compound beyond classic TRP channel activation.—Ewanchuk, B. W., Allan, E. R. O., Warren, A. L., Ramachandran, R., Yates, R. M. The cooling compound icilin attenuates autoimmune neuroinflammation through modulation of the T-cell response. FASEB J. 32,1236-1249 (2018). www.fasebj.org