TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice

Mechanisms underlying cold-induced immunosuppression remain unclear. Here we found that cold exposure leads to transient receptor potential melastatin 8 (TRPM8)-dependent, renin-angiotensin-aldosterone system (RAAS)-mediated hypertension, which subsequently induces small molecule and fluid extravasation, increases plasma Ig levels, and elicits immunosuppression. An effect is similar to the clinically-used immunosuppressive treatments of intravenous immunoglobulin (IVIg) against various inflammatory diseases, such as immune thrombocytopenia (ITP). Essential roles of TRPM8 and Ig in cold-induced immunosuppression are supported by the cold-mediated amelioration of ITP and the cold-mediated suppression of bacterial clearance, which were observed in wild-type mice but not in Ig- and TRPM8-deficient mutants. Treatment with antihypertensive drugs aliskiren and losartan drastically reversed high plasma Ig levels and ameliorated cold-induced immunosuppression, indicating the involvement of the RAAS and hypertension. These results indicated that the natively increased plasma Ig level is associated with immunosuppression during periods of cold exposure, and antihypertensive drugs can be useful to manage cold-induced immunosuppression.