Cholinergic Receptors Modulate Immune Complex–Induced Inflammation In Vitro and In Vivo

Abstract

Cholinergic neural output has been shown to modulate innate immune responses to infection, injury and ischemia through stimulation of α7 nicotinic acetylcholine receptors (α7nAChR) on mononuclear phagocytes. We tested the hypothesis that cholinergic neurotransmitters, similar to those released through activation of a neural reflex, regulate responses to products of the adaptive immune system, specifically immune complex (IC)–mediated activation of effector cells. In this study, we show that stimulation of α7nAChR on human polymorphonuclear neutrophils (PMNs) and blood mononuclear phagocytes in vitro attenuates C5aR- and FcγR-triggered generation of reactive oxygen species, expression of leukocyte markers involved in cell recruitment and adhesion, and release of TNF-α and other proinflammatory cytokines. We show that this pathway is operative in vivo. Ligation of cholinergic receptors blunts IC-triggered responses in the reverse peritoneal Arthus reaction in mice. The selective 7nAChR agonist GTS21 decreased PMN accumulation and release of cytokines and chemokines at sites of IC deposition. In addition, mice lacking α7nAChR had exaggerated responses to reverse peritoneal Arthus reaction characterized by increased infiltration of PMNs and elevated of levels of TNF-α and CXCL1 in peritoneal fluid compared with wild-type mice. Taken together, these findings suggest that cholinergic output has the potential to exert tonic inhibitory activity that dampens responses to ICs and C5a and thus may be a target to minimize tissue damage in autoimmune diseases.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Alzheimer's disease Phase 2 Comentis Briggs et al, 1995;Azuma et al, 1996Azuma et al, , 1999Mahnir et al, 1998;Li et al, 1999;Adams et al, 2000;Crutcher, 2000;Bruchfeld et al, 2010;Loram et al, 2010;Vukelic et al, 2013 Cognitive (Sydserff et al, 2009). In vivo, this compound exhibited activity in a variety of preclinical models including novel object recognition (NOR) in mouse, reversal of short-term memory deficits in fimbria-fornix-lesioned rats, and improvement in working memory in the spatial delayed response task in rhesus monkey (Sydserff et al, 2009;Castner et al, 2011;Werkheiser et al, 2011).…”

CHRNA7 inhibits cell invasion and metastasis of LoVo human colorectal cancer cells through PI3K/Akt signaling

“…Vukelic et al showed that cholinergic neurotransmitters (ACh), similar to those released through activation of a neural reflex, regulate responses to products of the adaptive immune system, specifically immune complex (IC)-mediated activation of effector cells (31). In particular, in both lung cancer and colon cancer, ACh acts as an autocrine growth factor for cancer growth and development (32)(33)(34).…”

“…A switch in the predominant nAChR subtype that is expressed on the cell membrane occurs during malignant transformation, which indicates that the effects of autocrine or paracrine ACh on cancer cells might differ from the effects on non-malignant cells, even if they are situated next to each other in the same tissue (21,31). Moreover, the diversity of nAChRs could be further increased by possible variants at the genomic or mRNA level.…”

The Protective Effect of Alpha 7 Nicotinic Acetylcholine Receptor Activation on Critical Illness and Its Mechanism

“…Nicotine was confirmed to inhibit neutrophils infiltration through reducing CXCL-1 and IL-8 levels 107, 108. In addition, studies showed that prevention of tissue injury by stimulating α7nAChR might be partly due to a decreased generation of neutrophils ROS by blunting FcγRs or C5aRs 104. Therefore, protective mechanisms of α7nAChR on neutrophils mainly aimed at migrating affected neutrophils to kill invading pathogens and alleviating tissue injury.…”

“…GTS-21 effectively modulated accumulation and activation of polymorphonuclear neutrophils (PMNs), α7nAChR -/- mice, however, showed uncontrolled PMN infiltration and excessive production of TNF-α and CXCL-1 in comparison with wild-type mice after being challenged with immune complex 104. Though a series of investigations showed that pro-inflammatory cytokines, TNF-α as an example, rendered neutrophils to accumulate in inflammatory sites, but simply lowering TNF-α production did not significantly inhibited neutrophils accumulation 105.…”