Carotid body sensing of systemic inflammation contributes to recruitment of the splanchnic anti-inflammatory pathway

• Systemic LPS increases splanchnic sympathetic nerve activity. • Carotid body ablation attenuates LPS-induced splanchnic sympathetic activation. • Disruption of carotid body input or splanchnic sympathetic outflow exacerbates LPS-induced inflammatory responses. • LPS drives RVLM neuronal activation in a carotid body–dependent manner. • Carotid bodies act as peripheral inflammatory sensors required for full engagement of the splanchnic anti-inflammatory pathway. Systemic inflammation engages autonomic reflexes that modulate immune responses, yet the peripheral sensors and central circuits responsible for recruiting sympathetic anti-inflammatory pathways remain incompletely defined. Here, we identify the carotid bodies as critical afferent sensors required for full engagement of a splanchnic sympathetic reflex during endotoxemia. Using in vivo splanchnic sympathetic nerve activity recordings, cytokine measurements, and brainstem neuronal mapping, we show that intraperitoneal injection of lipopolysaccharide (LPS) activates splanchnic sympathetic outflow and neurons within the rostral ventrolateral medulla (RVLM). Bilateral carotid body ablation markedly attenuated LPS-induced splanchnic sympathetic activation, reduced RVLM neuronal activation, and shifted cytokine responses toward a pro-inflammatory profile characterized by increased TNF-α and reduced IL-10 levels in plasma and spleen. Disruption of splanchnic efferent signaling similarly exacerbated inflammatory cytokine responses. Together, these findings suggest a carotid body–RVLM–splanchnic axis linking peripheral inflammatory signal detection to autonomic control of immune function during systemic inflammation.