Abstract
Transient Receptor Potential Melastatin-8 (TRPM8) reportedly plays a fundamental role in a variety of processes including cold sensation, thermoregulation, pain transduction and tumorigenesis. However, the role of TRPM8 in inflammation under cold conditions is not well known. Since cooling allows the convergence of primary injury and injury-induced inflammation, we hypothesized that the mechanism of the protective effects of cooling might be related to TRPM8. We therefore investigated the involvement of TRPM8 activation in the regulation of inflammatory cytokines. The results showed that TRPM8 expression in the mouse hypothalamus was upregulated when the ambient temperature decreased; simultaneously, tumor necrosis factor-alpha (TNFα) was downregulated. The inhibitory effect of TRPM8 on TNFα was mediated by nuclear factor kappa B (NFκB). Specifically, cold stress stimulated the expression of TRPM8, which promoted the interaction of TRPM8 and NFκB, thereby suppressing NFκB nuclear localization. This suppression consequently led to the inhibition of TNFα gene transcription. The present data suggest a possible theoretical foundation for the anti-inflammatory role of TRPM8 activation, providing an experimental basis that could contribute to the advancement of cooling therapy for trauma patients.
Highlights
Transient Receptor Potential Melastatin-8 (TRPM8) has been identified as a cold-activated non-selective cation channel expressed in a small population of peripheral sensory neurons[1,2]
TRPM8 in the central neuronal system of mice and its response to cold stress, mice were placed under cold conditions (4 °C) or normal conditions (25 °C)
The results showed that when pretreated with JSH-23 (8 μM)[20], the mRNA and protein expression levels of NFκB and TNFαin the wild type cells (WT) and knockdown cells (KD) cells were clearly downregulated after 3 hours of cold exposure, suggesting that the inhibitory effect of cold stress on TNFαwas mediated by NFκB (Fig. 6E–H)
Summary
Transient Receptor Potential Melastatin-8 (TRPM8) has been identified as a cold-activated non-selective cation channel expressed in a small population of peripheral sensory neurons[1,2]. TRPM8 is widely expressed in non-temperature-sensing organs[3,4,5,6,7]. Tissue cooling or hypothermia has been widely used to suppress tissue damage resulting from trauma, ischemia and surgery[15] and to inhibit inflammation[16,17]. These findings suggest that TRPM8 may possess an anti-inflammatory effect in certain circumstances. We observed that when the expression of TRPM8 in the mouse hypothalamus was upregulated in cold environments, TNFαexpression was downregulated
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