Transient Receptor Potential Ankyrin 1 (TRPA1) mediates IL-1β-Induced Thermoregulation

Abstract

Abstract TRPA1 is a non-specific cation channel, that has been previously implicated in temperature regulation and inflammation. Administration of TRPA1 agonists induce significant changes in body temperature. Similarly, IL-1β, a cytokine mediator of inflammation and injury, induces a significant change in body temperature. Here we reasoned that TRPA1 plays a role in IL-1β mediated temperature regulation. To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into the peritoneal cavity. Using chemogenetic technology, we generated a novel TRPA1-GqDREADD strain, in which TRPA1+ cells are activated by the administration of clozapine-N-oxide (CNO). Administration of CNO (ip) induces a significant change in body temperature (vehicle vs. CNO; 674.3 ± 29.3 AUC vs. 1646 ± 172 AUC; Welch’s T-test; p<.001). To determine if TRPA1 is responsible for IL-1β induced thermoregulation, wild type mice and TRPA1 KO mice were injected with IL-1β (5.0μg/kg, ip). As expected, wildtype mice had a significant change in body temperature. However, this response was significantly impaired in TRPA1 KO mice (wild type vs. TRPA1 KO; 1045 ± 35.29 AUC vs. 577.9 ± 26.13 AUC; Welch’s T-test; p<0.0001). To investigate whether selective TRPA1 expression in neurons is required for IL-1β-induced thermoregulation, we generated Syn-Cre/TRPA1fl/fl mice selectively devoid of TRPA1 expression in neurons. Selective ablation of TRPA1-expression in neurons significantly attenuates IL-1β-induced changes in body temperature (wild type vs. Syn-Cre/TRPA1fl/fl; 1082 ± 61.49 AUC vs. 775.8 ± 66.89 AUC Welch’s T-test; p<0.01). Together, these studies indicate that IL-1β-induced thermoregulation is mediated via neuronal TRPA1. Supported by grant from NIH to KJT and SSC