Neuroimmunomodulation of tissue injury and disease: an expanding view of the inflammatory reflex pathway

Figures

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  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…

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  Fig. 2. Another anti-inflammatory pathway elicited by afferent vagus nerve stimulation. Afferent vagus nerve stimulation can elicit an anti-inflammatory pathway involving sympathetic efferents through the central nervous system (CNS). In a model of joint inflammation, the local release of norepinephrine from sympathetic nerve terminals within joints alleviates inflammation. On the other hand, the splanchnic sympathetic nerve seems to be important to suppress systemic inflammation after lipopolysaccharide administration. Direct target(s) of the splanchnic nerve is not clear. NTS, nucleus tractus solitarius