Manipulation of the inflammatory reflex as a therapeutic strategy

Abstract

The cholinergic anti-inflammatory pathway is the efferent arm of the inflammatory reflex, a neural circuit through which the CNS can modulate peripheral immune responses. Signals communicated via the vagus and splenic nerves use acetylcholine, produced by Choline acetyltransferase (ChAT)+ T cells, to downregulate the inflammatory actions of macrophages expressing α7 nicotinic receptors. Pre-clinical studies using transgenic animals, cholinergic agonists, vagotomy, and vagus nerve stimulation have demonstrated this pathway's role and therapeutic potential in numerous inflammatory diseases. In this review, we summarize what is understood about the inflammatory reflex. We also demonstrate how pre-clinical findings are being translated into promising clinical trials, and we draw particular attention to innovative bioelectronic methods of harnessing the cholinergic anti-inflammatory pathway for clinical use.

Keywords: cholinergic anti-inflammatory pathway; inflammatory disease; inflammatory reflex; vagus nerve stimulation; α7 nicotinic acetylcholine receptor.

Graphical abstract

Figure 1

The cholinergic anti-inflammatory pathway Through the inhibition of splenic macrophages, the vagus nerve attenuates inflammatory responses in multiple bodily systems, including the lungs, GIT, myocardium, synovia, and kidneys. The vagus nerve may also mediate some of its effects directly through innervation of viscera (e.g., lungs, heart, GIT). Suppression of the systemic inflammatory response can likewise influence neuroinflammation. ACH, acetylcholine; NA, noradrenaline.

Figure 2

Proposed intracellular mechanisms of the α7nAChR AC6, adenylyl cyclase 6; Ach, acetylcholine; AMP, adenosine monophosphate; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; JAK2, Janus kinase 2; MAPK, mitogen-activated protein kinase; miRNA, microRNA; NF-κB, nuclear factor κ-B; NLRP3, NOD-, LRR-, and pyrin domain-containing protein; STAT3, signal transducer and activator of transcription 3.

Figure 3

Stimulation of the CAP The CAP can be stimulated pharmacologically through centrally acting acetylcholinesterase inhibitors (AChEI) and peripherally acting nicotine or α7nAChR agnoists. Non-pharmacological stimulation is achieved through invasive and non-invasive VNS or pUS. iVNS, invasive vagus nerve stimulation; taVNS, transauricular vagus nerve stimulation; tcVNS, transcervical Vagus nerve stimulation.