Acetylcholine-treated murine dendritic cells promote inflammatory lung injury.

Soledad Gori,Jorge Geffner,Carolina Jancic,Silvia Vanzulli,Gabriela Salamone,Julieta Alcain,Mónica Vermeulen,Mariela A Moreno Ayala,Marianela Candolfi,Bernhard Ryffel

doi:10.1371/journal.pone.0212911

Abstract

In recent years a non-neuronal cholinergic system has been described in immune cells, which is often usually activated during the course of inflammatory processes. To date, it is known that Acetylcholine (ACh), a neurotransmitter extensively expressed in the airways, not only induces bronchoconstriction, but also promotes a set of changes usually associated with the induction of allergic/Th2 responses. We have previously demonstrated that ACh polarizes human dendritic cells (DC) toward a Th2-promoting profile through the activation of muscarinic acetylcholine receptors (mAChR). Here, we showed that ACh promotes the acquisition of an inflammatory profile by murine DC, with the increased MHC II IAd expression and production of two cytokines strongly associated with inflammatory infiltrate and tissue damage, namely TNF-α and MCP-1, which was prevented by blocking mAChR. Moreover, we showed that ACh induces the up-regulation of M3 mAChR expression and the blocking of this receptor with tiotropium bromide prevents the increase of MHC II IAd expression and TNF-α production induced by ACh on DC, suggesting that M3 is the main receptor involved in ACh-induced activation of DC. Then, using a short-term experimental murine model of ovalbumin-induced lung inflammation, we revealed that the intranasal administration of ACh-treated DC, at early stages of the inflammatory response, might be able to exacerbate the recruitment of inflammatory mononuclear cells, promoting profound structural changes in the lung parenchyma characteristic of chronic inflammation and evidenced by elevated systemic levels of inflammatory marker, TNF-α. These results suggest a potential role for ACh in the modulation of immune mechanisms underlying pulmonary inflammatory processes.

Highlights

Because the lung is an organ that is largely exposed to microenvironmental stimuli such as microbes, allergens and pollution, the local presence of antigen-presenting cells, such as dendritic cells (DC), is crucial for the initiation and maintenance of mucosal immunity in the respiratory tract
We aimed to evaluate whether ACh acting on DC affects the early development of the inflammatory response in the lung, and based on our previous results in human DC [9,16], we first assessed whether this neurotransmitter is able to modulate the phenotypic and functional profile of murine DC
To described in human DC [9], we found that ACh markedly stimulated the production of TNF-α without modifying the spontaneous production of IL-12p70 and IL-10 (Fig 3C and 3D)

Summary

Introduction

Because the lung is an organ that is largely exposed to microenvironmental stimuli such as microbes, allergens and pollution, the local presence of antigen-presenting cells, such as dendritic cells (DC), is crucial for the initiation and maintenance of mucosal immunity in the respiratory tract. Besides pathogen-associated molecular patterns and cytokines, other stimuli are capable to modulate DC function [1]. In recent years it has become evident there is interaction between the nervous and immune systems [2,3,4]. Acetylcholine (ACh) represents the most important neurotransmitter of the parasympathetic nervous system. This molecule is largely expressed in the airways, where it induces smooth muscle contraction [5,8]. We have recently demonstrated that ACh polarizes DC toward a Th2-promoting profile through the activation of muscarinic acetylcholine receptors (mAChR) [9]. Buhling et al have shown that ACh-induced release of chemotactic mediators from inflammatory cells could be inhibited by tiotropium bromide (Tio), a selective M3 mAChR antagonist [10]

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