Abstract
Inflammation is a crucial defense mechanism that protects the body from the devastating effects of invading pathogens. However, an unrestrained inflammatory reaction may result in systemic manifestations with dire consequences to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. Previously, we demonstrated that cholinergic stimulation confers enhanced protection in experimental animals orally infected with virulent Salmonella enterica serovar Typhimurium. In this study, we investigated the mechanism by which this enhanced protection takes place. Cholinergic stimulation was induced by a 3-week pretreatment with paraoxon, a highly specific acetylcholinesterase (AChE) inhibitor. This treatment enhanced host survival following oral-route infection and this correlated with significantly reduced bacterial load in systemic target organs. Enhanced protection was not due to increased gut motility or rapid bacterial clearance from the gastrointestinal tract. Moreover, protection against bacterial infection was not evident when the animals were infected systemically, suggesting that acetylcholine-mediated protective effect was mostly confined to the gut mucosal tissue. In vivo imaging demonstrated a more localized infection and delay in bacterial dissemination into systemic organs in mice pretreated with paraoxon. Morphological analysis of the small intestine (ileum) showed that AChE inhibition induced the degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrate a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against oral pathogens.
Highlights
Various animal models have elucidated direct interplay between immune and nervous systems in controlling inflammation
Acetylcholinesterase is an enzyme responsible for terminating the action of the neurotransmitter acetylcholine. Inhibition of this enzyme leads to an increase or accumulation of ACh in the synaptic clefts, inducing a cholinergic stimulation that is widely used for the treatment of neurodegenerative diseases such as Alzheimer’s and myasthenia gravis [45, 46]
Cholinergic stimulation by AChE inhibitors can modulate the immune response to autoantigens in different animal models of diabetes [24, 47]
Summary
Various animal models have elucidated direct interplay between immune and nervous systems in controlling inflammation. The physiological mechanism through which the vagus nerve controls the immune response to inflammation has been named the inflammatory reflex” [1, 2]. PC are present in the crypts of Lieberkuhn, in the distal part of the small intestine, and are rich in secretory granules containing microbicidal peptides and proteins such as lysozyme, phospholipase A, cryptdins, cryptdin-related sequence peptides (CRS), and angiogenin-4 (Ang-4). These factors contribute to intestinal innate immunity by bacterial sequestering and limiting pathogen penetration and dissemination [5, 6]. Immune cells (macrophages and DC) located between the epithelial cells of the mucosal barrier recognize trespassing pathogens as foreigners and produce inflammatory cytokines and chemokines to recruit immune cells to the site of injury [7]
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