IL‐1β‐Induced Thermoregulation and Vagus Nerve Activity is Mediated by Transient Receptor Potential Ankyrin 1

Intraperitoneal administration of interleukin-1β (IL-1β), a cytokine mediator of inflammation and injury, induces afferent vagus nerve signaling and brain-mediated sickness syndrome. However, the mechanism of IL-1β signaling through the vagus nerve is unknown. Here we show that transient receptor potential ankyrin 1 (TRPA1) expression in sensory vagus neurons is required to mediateIL-1β-induced thermoregulation and vagus nerve activation. We monitored body temperature in conscious and unrestrained mice by radiotelemetry using probes implanted into peritoneal cavity. Intraperitoneal administration of IL-1β induced a significant change in body temperature in wild type mice. However, this response was significantly impaired in TRPA1 knock out mice (TRPA1 KO) (wild type vs. TRPA1 KO; 1045 ± 35.29 AUC vs. 577.9 ± 26.13 AUC; t-test with Welch's correction; 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; t-test with Welch's correction; p<0.01). We have previously shown IL-1β induces sensory signaling by recording vagus nerve activity. Accordingly, here we collected extra-neural recordings from the cervical vagus nerve and as expected observed administration of IL-1β induced a significant increase in vagus nerve activity (total spikes 5 minutes pre- and post-administration: 85.6 ± 0.17 spikes vs. 9998.0 ± 3617.0 spikes; t-test; p<0.01). Moreover, no significant changes in vagus nerve activity occurred in TRPA1 KO mice (pre vs post-administration: 867.3 ± 395.7 spikes vs. 1069.0 ± 455.8 spikes, t-test, N.S.), and in Syn-Cre/TRPA1fl/fl mice (pre vs post-administration: 2179.0 ± 558.8 spikes vs. 1996.0 ± 460.8 spikes; t-test; N.S.). Whole-cell patch-clamp recordings and calcium imaging revealed TRPA1 is required to mediate IL-1β-dependent activation of vagus sensory neurons. Together, these studies indicate IL-1β-induced thermoregulation and vagus nerve activation is mediated by TRPA1.