A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity

Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation

“…Procainamide and hydralazine, 2 medications definitively implicated in cases of drug-induced autoimmunity, trigger NET formation, while minocycline and clozapine, 2 medications less commonly implicated in drug-induced autoimmunity, do not. These observations, in combination with the previously reported associations of propylthiouracil (6) and levamisole (7) with NETosis, strongly suggest that NETosis is involved in the pathogenesis of drug-induced autoimmunity, possibly through the externalization and modification of intracellular autoantigens.…”

“…We previously demonstrated that neutrophils possess muscarinic receptors that can be activated by acetylcholine or levamisole to induce NET formation, and that surface cholinergic receptors are more abundant in neutrophils from patients with SLE (7). In this study, we have shown that procainamide also triggers muscarinic receptors on neutrophils to promote NETosis.…”

“…Screening analysis showed that procainamide and hydralazine did not stimulate any human TLRs (Figure D). Levamisole, a known cause of drug‐induced autoimmunity, can trigger NET formation via engagement of muscarinic receptors on the surface of neutrophils . NETs induced by procainamide, but not by hydralazine, were inhibited by atropine (nonspecific muscarinic receptor antagonist) and by M 1 /M 3 muscarinic subtype receptor antagonists (Figure E).…”

“…Screening analysis showed that procainamide and hydralazine did not stimulate any human TLRs ( Figure 2D). Levamisole, a known cause of drug-induced autoimmunity, can trigger NET formation via engagement of muscarinic receptors on the surface of neutrophils (7). NETs induced by procainamide,…”

Clinical associations between acetylcholine levels and cholinesterase activity in saliva and gingival crevicular fluid and periodontal diseases

“…However, evidence from in vivo and in vitro infection models suggests that it is too simplistic to state that within complex mucosal tissues ACh acts purely in an anti-inflammatory capacity (Giebelen, Leendertse, Florquin, & van der Poll, 2009;Giebelen et al, 2008;Rajendran et al, 2015). There is indeed evidence to support a role for ACh in promoting neutrophil recruitment, activation and neutrophil extracellular trap (NET) formation (Carmona-Rivera et al, 2017;Giebelen et al, 2008;Rajendran et al, 2015;Ruhnau et al, 2014;Xu et al, 2008). A plausible explanation for these differential findings is the fact that immune cells possess a plethora of nicotinic and muscarinic receptors which may differentially regulate immune responses.…”