Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium

Abstract

SummaryThe cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

“…Thus, in a recent randomized controlled trial, critically ill patients with delirium receiving a cholinesterase inhibitor (rivastigmine) had greater mortality than participants not treated with this drug . Alternatively, recent experimental evidence shows that administration of AChE inhibitors suppresses systemic inflammation and enhances survival of animals exposed to lipopolysaccharides or infection . These conflicting results demonstrate that any modulation of the cholinergic system should take into account the complex regulatory mechanisms determining the participant's baseline immune set point and the magnitude of responsiveness to inflammatory challenge.…”

The Effect of Cholinesterase Activity on the Diagnosis and Prognosis of Sepsis

“…Chiarla and colleagues identified a significant decrease in the cholinesterase activity of patients in a critical condition, in particular, patients with sepsis or liver dysfunction [30]. Fernandez-Cabezudo and colleagues have shown that cholinergic stimulation of the immune system has a protective effect against salmonella infections [31].…”

Nutritional Regulation of Gut Barrier Integrity in Weaning Piglets

“…The nervous system is also a regulator of GIT immune responses via neuro-immune synapses, via the modulation of bacterial toxin detection or adherence [34,35]. Some authors have found that stress neuroendocrine mediators such as catecholamine and the adrenocorticotropic hormone (ACTH) can influence the binding and adherence of pig enteric pathogens to the intestinal mucosa [34][35][36][37][38]. Medland et al [39] found significant alterations in ENS phenotype and function in response to weaning.…”