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

Shinji Tanaka, Benjamin Hammond, Diane L Rosin, Mark D Okusa, Shinji Tanaka, Benjamin Hammond, Diane L Rosin, Mark D Okusa

Abstract

Neuroimmunomodulation through peripheral nerve activation is an important therapeutic approach to various disorders. Central to this approach is the inflammatory reflex pathway in which the cholinergic anti-inflammatory pathway represents the efferent limb. Recent studies provide a framework for understanding this control pathway, however our understanding remains incomplete. Genetically modified mice, using optogenetics and pharmacogenomics, have been invaluable resources that will allow investigators to disentangle neural pathways that provide a unifying mechanism by which vagal nerve stimulation (and other means of stimulating the pathway) leads to an anti-inflammatory and tissue protective effect. In this review we describe disease models that contribute to our understanding of how vagal nerve stimulation attenuates inflammation and organ injury: acute kidney injury, rheumatoid arthritis, and inflammatory gastrointestinal disease. The gut microbiota contributes to health and disease and the potential role of the vagus nerve in affecting the relationship between gut microbiota and the immune system and modifying diseases remains an intriguing opportunity to attenuate local and systemic inflammation that undergird disease processes.

Keywords: Acute kidney injury; Cholinergic anti-inflammatory pathway; Colitis; Gut microbiota; Rheumatoid arthritis.

Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

© The Author(s) 2019.

Figures

Fig. 1
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
Fig. 2
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

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