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

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

doi:10.18632/oncotarget.24356

Hao Chan, Hsin-Hou Chang + Show 4 more

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https://doi.org/10.18632/oncotarget.24356

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Abstract

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.

Highlights

The ancient physicians Hippocrates (460–370 BC) and Zhang Zhongjing (150–219 AD) have documented the relationship between diseases and cold exposure [1, 2]
Gene expression analysis by quantitative reverse transcriptionpolymerase chain reaction revealed that renin–angiotensin–aldosterone system (RAAS) components, such as renin, angiotensin II receptors AT1a, AT1b, AT2 and angiotensin converting enzyme (ACE), all markedly increased after 4 h cold exposure (Supplementary Figure 2A)
These results collectively suggest that cold exposure can induce acute RAASmediated hypertension within 1 h, and such hypertension is sustainable for hours in mice (Figure 1B and 1C)

Summary

Introduction

The ancient physicians Hippocrates (460–370 BC) and Zhang Zhongjing (150–219 AD) have documented the relationship between diseases and cold exposure [1, 2]. Many recent studies have reported that respiratory tract infections, pneumonia, and the outbreak of influenza viruses are associated with seasonal reductions in temperature [3,4,5,6]. Despite hundreds of years of study, the mechanisms underlying cold exposure-associated infections and the related immune system disturbances remain elusive; millions of people are still affected by seasonal infections every year [7]. Various hypotheses have been postulated to explain cold exposure-induced immunosuppression. Studies have suggested that cold exposure can result in the production of immunosuppressive corticosteroids through the hypothalamic–pituitary–adrenal (HPA) axis [8, 9]. Another study suggested that a drop in the temperature reduces local circulation and restricts the functioning of leukocytes in the upper airway tract [10]. The detailed mechanism and its effect on immunosuppression require additional investigation

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