The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection

Darby, Matthew; Schnoeller, Corinna; Vira, Alykhan; Culley, Fiona J.; Bobat, Saeeda; Logan, Erin; Kirstein, Frank; Wess, Jürgen; Cunningham, Adam F.; Brombacher, Frank; Selkirk, Murray E.; Horsnell, William G. C.

doi:10.1371/journal.ppat.1004636

Cited by 45 publications

(31 citation statements)

References 41 publications

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“…Of increasing interest, type 3 muscarinic receptors (M3Rs) have received significant attention for their key role in maintaining mucosal barrier function (122) and in regulating mucin production and secretion within the GI tract (123). In addition, M3Rs contribute to host defense against N. brasiliensis (124,125) and C. rodentium (121). Despite N. brasiliensis infection, mice deficient in the muscarinic acetylcholine receptor M3 (Chrm3 −/− ) show an absence of typical goblet cell expansion (125).…”

Section: Enteric Nervous System Regulationmentioning

confidence: 99%

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

et al. 2020

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Throughout the gastrointestinal (GI) tract, a distinct mucus layer composed of highly glycosylated proteins called mucins plays an essential role in providing lubrication for the passage of food, participating in cell signaling pathways and protecting the host epithelium from commensal microorganisms and invading pathogens, as well as toxins and other environmental irritants. These mucins can be broadly classified into either secreted gel-forming mucins, those that provide the structural backbone for the mucus barrier, or transmembrane mucins, those that form the glycocalyx layer covering the underlying epithelial cells. Goblet cells dispersed among the intestinal epithelial cells are chiefly responsible for the synthesis and secretion of mucins within the gut and are heavily influenced by interactions with the immune system. Evidence from both clinical and animal studies have indicated that several GI conditions, including inflammatory bowel disease (IBD), colorectal cancer, and numerous enteric infections are accompanied by considerable changes in mucin quality and quantity. These changes include, but are not limited to, impaired goblet cell function, synthesis dysregulation, and altered post-translational modifications. The current review aims to highlight the structural and functional features as well as the production and immunological regulation of mucins and the impact these key elements have within the context of barrier function and host defense in intestinal inflammation.

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Section: Enteric Nervous System Regulationmentioning

confidence: 99%

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

et al. 2020

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“…Cholinergic signalling suppresses expression of inflammatory cytokines by macrophages via α7 nicotinic receptors (nα7R) [33], whereas ligation of the m3 muscarinic receptor (m3R) on CD4+ T cells potentiates cellular activation and cytokine production [11]. It was thus unclear what effect secreted AChEs might have on the immune response to an infectious agent.…”

Section: Discussionmentioning

confidence: 99%

“…B cells also release ACh which acts on endothelial cells to inhibit expression of integrins and thus suppress inflammatory extravasation of neutrophils [10]. In contrast to these anti-inflammatory effects of ACh on innate immunity, we recently showed that ACh acts as a co-stimulatory signalling molecule for CD4+ T cell activation and cytokine production [11]. Cholinergic signalling in relation to immunity is thus complex and multi-layered, and it is difficult to predict what effect parasite secreted AChEs might have in vivo.…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

et al. 2016

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Nematode parasites secrete molecules which regulate the mammalian immune system, but their genetic intractability is a major impediment to identifying and characterising the biological effects of these molecules. We describe here a novel system for heterologous expression of helminth secreted proteins in the natural parasite of mice, Trypanosoma musculi, which can be used to analyse putative immunomodulatory functions. Trypanosomes were engineered to express a secreted acetylcholinesterase from Nippostrongylus brasiliensis. Infection of mice with transgenic parasites expressing acetylcholinesterase resulted in truncated infection, with trypanosomes cleared early from the circulation. Analysis of cellular phenotypes indicated that exposure to acetylcholinesterase in vivo promoted classical activation of macrophages (M1), with elevated production of nitric oxide and lowered arginase activity. This most likely occurred due to the altered cytokine environment, as splenocytes from mice infected with T. musculi expressing acetylcholinesterase showed enhanced production of IFNγ and TNFα, with diminished IL-4, IL-13 and IL-5. These results suggest that one of the functions of nematode secreted acetylcholinesterase may be to alter the cytokine environment in order to inhibit development of M2 macrophages which are deleterious to parasite survival. Transgenic T. musculi represents a valuable new vehicle to screen for novel immunoregulatory proteins by extracellular delivery in vivo to the murine host.

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“…Cholinergic signaling plays a role in a number of immune cell functions, including acting as a costimulatory factor for T lymphocyte activation and cytokine secretion (Darby et al . ), and there are many ways in which AChEs could inhibit or modulate these responses. Alternatively, secreted AChEs could protect against inhibitors ingested in foodstuffs, i.e.…”

Section: Amplification Of Ache Genes In Parasitic Nematodesmentioning

confidence: 99%

Natural genomic amplification of cholinesterase genes in animals

Chatonnet

Lenfant

Marchot

et al. 2017

Journal of Neurochemistry

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Tight control of the concentration of acetylcholine at cholinergic synapses requires precise regulation of the number and state of the acetylcholine receptors, and of the synthesis and degradation of the neurotransmitter. In particular, the cholinesterase activity has to be controlled exquisitely. In the genome of the first experimental models used (man, mouse, zebrafish and drosophila), there are only one or two genes coding for cholinesterases, whereas there are more genes for their closest relatives the carboxylesterases. Natural amplification of cholinesterase genes was first found to occur in some cancer cells and in insect species subjected to evolutionary pressure by insecticides. Analysis of the complete genome sequences of numerous representatives of the various metazoan phyla show that moderate amplification of cholinesterase genes is not uncommon in molluscs, echinoderms, hemichordates, prochordates or lepidosauria. Amplification of acetylcholinesterase genes is also a feature of parasitic nematodes or ticks. In these parasites, over-production of cholinesterase-like proteins in secreted products and the saliva are presumed to have effector roles related to host infection. These amplification events raise questions about the role of the amplified gene products, and the adaptation processes necessary to preserve efficient cholinergic transmission.

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The M3 Muscarinic Receptor Is Required for Optimal Adaptive Immunity to Helminth and Bacterial Infection

Cited by 45 publications

References 41 publications

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

Mucins in Intestinal Mucosal Defense and Inflammation: Learning From Clinical and Experimental Studies

Modulation of the Immune Response by Nematode Secreted Acetylcholinesterase Revealed by Heterologous Expression in Trypanosoma musculi

Natural genomic amplification of cholinesterase genes in animals

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