The cholinergic anti-inflammatory pathway depicted. Scheme of the vagus nerve interacting with immune activation at multiple levels following ingestion, infection, and trauma. (1) During digestion, the commensal flora and dietary components activate the sensory afferent vagus nerve, which will transmit the information to the brain. In return, the brain may activate the efferent vagus nerve to modulate gastrointestinal macrophages. (2) The efferent vagus nerve also modulates systemic inflammatory responses through a mechanism involving an intact spleen. Upon infection or trauma, bacterial components or intracellular mediators (HMGB1, heat shock proteins, etc.) activate macrophages to produce proinflammatory cytokines. (3) This will trigger afferent vagus nerve signaling. (4) Central activation of vagal efferent pathways which lead to release of acetylcholine (ACh) and relay on peripheral ganglia to stimulate adrenergic transmitter release (in the spleen) to act on aplenic antigen presenting cells and macrophages. Recent data indicate the generation of ChAT-positive ACh producing immune cells (see text). Interrogation marks indicate that, although macrophages are found in the proximity of cholinergic fibers in the spleen and the intestine, there is currently no evidence demonstrating that parasympathetic neurons, indeed, innervate immune cells in the gut wall. HMGB1: high-mobility group box 1.