Role of TRPM8 in switching between fever and hypothermia in adult mice during endotoxin-induced inflammation

Chinatsu Shiraki,Ririka Horikawa,Yuzuki Oe,Momoka Fujimoto,Kaho Okamoto,Erkin Kurganov,Seiji Miyata

doi:10.1016/j.bbih.2021.100291

Chinatsu Shiraki, Ririka Horikawa + Show 5 more

Open Access

https://doi.org/10.1016/j.bbih.2021.100291

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Abstract

Transient receptor potential melastatin 8 (TRPM8) functions in the sensing of noxious and innocuous colds; however, its significance in pathogen-induced thermoregulation remains unclear. In the present study, we investigated the role of TRPM8 in the regulation of endotoxin-induced body temperature control. The peripheral administration of low-dose lipopolysaccharide (LPS) at 50 μg/kg generated fever in wild-type (WT) mice, whereas it caused hypothermia in TRPM8 knockout (KO) animals. LPS-induced sickness responses such as decrease in body weight, and food and water intake were not different between WT and TRPM8 KO mice. TRPM8 KO mice exhibited more severe hypothermia and lower locomotor activity following the peripheral administration of high-dose LPS at 5 mg/kg compared with WT ones. An intracerebroventricular (i.c.v.) injection of either LPS at 3.6 μg/kg or interleukin-1β at 400 ng/kg elicited hypothermia in TRPM8 KO mice, in contrast to fever in WT animals. The peripheral administration of zymosan at 3 mg/kg also induced hypothermia in contrast to fever in WT mice. An i.c.v. injection of prostaglandin E2 at 16 or 160 nmol/kg induced normal fever in both WT and TRPM8 KO mice. Infrared thermography showed significant decline of the interscapular skin temperature that estimates temperature of the brown adipose tissue, regardless of no alteration of its temperature in WT animals. Fos immunohistochemistry showed stronger Fos activation of hypothalamic thermoregulation-associated nuclei in TRPM8 KO mice compared with WT animals following the peripheral administration of low-dose LPS. Therefore, the present study indicates that TRPM8 is necessary for switching between fever and hypothermia during endotoxin-induced inflammation.

Highlights

The recognition of pathogen infections is one of the most important mechanisms of innate immunity for eliminating pathogens and the first line of host defense against infection (Thaiss et al, 2016)
The number of Fos-expressing neurons in hypothalamic thermoregulation-associated regions was significantly higher in Transient receptor potential melastatin 8 (TRPM8) KO mice than in WT animals after the peripheral administration of lowdose LPS. These results indicate that central TRPM8 plays a crucial function in switching between fever and hypothermia during endotoxininduced inflammation, and propose a new aspect for infection-induced body temperature regulation in human
There was no significant difference of TLR4 expression in the circumventricular organs (CVOs) and arcuate nucleus between WT and TRPM8 KO mice using the immunohistochemistry (Fig. S1)

Summary

Introduction

The recognition of pathogen infections is one of the most important mechanisms of innate immunity for eliminating pathogens and the first line of host defense against infection (Thaiss et al, 2016). The infection-induced activation of immune cells via TLRs leads to a broad spectrum of sickness symptoms, such as body temperature changes, nausea, decreased appetite, malaise, and fatigue, which are adaptive responses to promote animal survival (McCusker and Kelley, 2013). Fever enhances immunoprotective mechanisms in both the innate and adaptive immune systems, such as the acceleration of cytokine production and the cellular cytotoxic activity of dendritic cells, natural killer cells, macrophages as well as signaling by and the differentiation of T cells (Evans et al, 2015). Fever results in an increased metabolic rate, with only a 1 C increase in body temperature elevating the metabolic rate by approximately 10% (Kluger, 1979)

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