The cholinergic anti-inflammatory pathway: A critical review

Abstract

From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

“…In addition, hematopoietic α7 nicotinic acetylcholine receptors (α7nAChR, encoded by Chrna7) and sympathetic innervation of the spleen are required for US-induced protection (8). These facts are consistent with stimulation of the inflammatory reflex called the cholinergic antiinflammatory pathway (CAP) (9,10). This pathway modulates innate and adaptive immunity, and modulation of the reflex is effective in various inflammatory disease models (11).…”

“…VNS was reported to induce or increase the production of ACh, the endogenous α7nAChR agonist, by a splenic CD4 + T cell subset (15). Thus, the roles of spleen, α7nAChRs, inflammatory cytokines, and immune cells are shared by US and VNS (7,10,31). Considering these similarities, we conclude that the splenic CAP, which includes ChATpositive T cells that synthesize ACh (15,32), α7nAChR-positive macrophages (26), and subsequent downstream effects, is activated both by US and by VNS.…”

“…Because beta blockers and spleen denervation reduce the antiinflammatory effect elicited by vagal stimulation, an alternative hypothesis posits that the CAP is elicited via the sympathetic system and that VNS may activate the splenic nerve via a vagosympathetic reflex (10). Clearly, under anesthesia, vagal afferent stimulation evokes a response in sympathetic nerves and this response does have an excitatory component (29).…”

“…As part of the CAP (13)(14)(15), acetylcholine-producing (ACh-producing) lymphocytes might have an important role. Although the intervening steps between VNS and splenic activation are not clearly defined (10,16), norepinephrine (NE) that is released from the splenic sympathetic nerve binds to β2-adrenergic receptors (β2AR) on nearby choline acetyltransferase-expressing (ChAT-expressing) splenic memory T cells (CD4 + CD44 hi CD62L lo ) and B cells (17). This subset of splenic ACh-producing T cells likely activates adjacent splenic macrophages via the α7nAChR (15), which leads to suppression of proinflammatory cytokines.…”

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

“…a7 is an important player in the "cholinergic antiinflammatory pathway," which is a link between vagal efferent fibers and innate immune system (Martelli et al, 2014). a7 modulates intracellular signal pathways [Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT3) and PI3K/Akt] in immune cells, which results in potent anti-inflammatory effects through cytokine production inhibition and overexpression of heme oxygenase 1 (Báez-Pagán et al, 2015;Egea et al, 2015) (Fig.…”