C1 neurons mediate a stress-induced anti-inflammatory reflex in mice

C1 neurons (C1), located in the medulla oblongata, mediate adaptive autonomic responses to physical stressors (e.g. hypotension, hemorrhage, lipopolysaccharide). We describe here a powerful effect of restraint stress mediated by C1: protection against renal ischemia-reperfusion injury (IRI). Restraint stress or optogenetic C1 stimulation (10 min) protected mice from IRI. The protection was reproduced by injecting splenic T-cells pre-incubated with noradrenaline or splenocytes harvested from stressed mice. Stress-induced IRI protection was absent in α7nAChR(−)(/)(−) mice and greatly reduced by destroying or transiently inhibiting C1. The protection conferred by C1 stimulation was eliminated by splenectomy, ganglionic blocker administration, or β(2)-adrenergic receptor blockade. Although C1 stimulation elevated plasma corticosterone and increased both vagal and sympathetic nerve activity, C1-mediated IRI protection persisted after subdiaphragmatic vagotomy or corticosterone receptor blockade. In conclusion, acute stress attenuates IRI by activating a cholinergic, predominantly sympathetic, anti-inflammatory pathway. C1 neurons are necessary and sufficient to mediate this effect.