Research Papers:

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

Hao Chan, Hsuan-Shun Huang, Der-Shan Sun, Chung-Jen Lee, Te-Sheng Lien and Hsin-Hou Chang _

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Oncotarget. 2018; 9:12781-12795. https://doi.org/10.18632/oncotarget.24356

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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

Correspondence to:

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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