TRPM8 and RAAS-mediated hypertension is critical for cold-induced immunosuppression in mice
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Hao Chan1,*, Hsuan-Shun Huang2,*, Der-Shan Sun1,3,*, Chung-Jen Lee4,*, Te-Sheng Lien3 and Hsin-Hou Chang1,3
1Institute of Medical Sciences, Tzu-Chi University, Hualien, Taiwan
2Center for Prevention and Therapy of Gynecological Cancers, Department of Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
3Department of Molecular Biology and Human Genetics, Tzu-Chi University, Hualien, Taiwan
4Department of Nursing, Tzu Chi College of Technology, Hualien, Taiwan
*These authors contributed equally to this work
Hsin-Hou Chang, email: [email protected]
Keywords: cold exposure; TRPM8; immunosuppression; renin–angiotensin–aldosterone system; hypertension
Received: August 15, 2017 Accepted: January 25, 2018 Published: January 30, 2018
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.
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