Fig. 1

The inflammatory reflex. The inflammatory reflex is triggered when the afferent vagus nerve senses inflammatory products through the receptors. The nerve activity is relayed through the central nervous system (CNS) to the efferent vagus nerve. The original pathway involves the splenic nerve although a direct connection between the efferent vagus nerve and the splenic nerve is still controversial. Activated splenic nerves release norepinephrine from their terminals, which interacts with β2-adrenergic receptors expressed on the choline acetyltransferase (ChAT)-positive T cells in the spleen, causing acetylcholine (ACh) release from this specific T cell subpopulation. ACh binds to α7 nicotinic acetylcholine receptors (α7nAChRs) expressed on macrophages residing in close proximity to ChAT-positive T cells, resulting in suppression of proinflammatory cytokine production (e.g., TNFα) by macrophages and alleviated inflammation in many pathological settings (e.g., endotoxemia, acute kidney injury). Recent studies also suggested that a direct interaction between cholinergic enteric neurons and gut resident macrophages via ACh had an anti-inflammatory effect. DMV, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius