Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection

Labed, Sid Ahmed; Wani, Khursheed Ahmad; Jagadeesan, Sakthimala; Hakkim, Abdul; Najibi, Mehran; Irazoqui, Javier E.

doi:10.1016/j.immuni.2018.04.017

Cited by 69 publications

(61 citation statements)

References 88 publications

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“…The enteric nervous system is considered part of this niche 2 , and acetylcholine (Ach), as the most predominant enteric neurotransmitter 3 , exerts its functions by acting on nicotinic or muscarinic receptors on target cells 4 . Enteric neurons modulate epithelial proliferation 5 via muscarinic receptors 6,7 and muscarinic signaling has been shown to act on intracellular pathways, such as Wnt 8 or trans-activate EGFR 9 . However, the influence of cholinergic signaling on ISC activity and differentiation remains to be clarified.…”

mentioning

confidence: 99%

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

et al. 2020

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The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.

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confidence: 99%

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

et al. 2020

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“…We have earlier shown that non cell autonomous control of immunity by the nervous system, during P. aeruginosa infection, impinges on p38 MAPK pathway and noncanonical UPR pathways (Sun et al, 2011;Cao et al, 2017). C. elegans has approximately 120 cholinergic neurons and these can activate wnt signalling in the intestine in response to infection by S. aureus (Irazoqui et al, 2008;Labed et al, 2018). Our study showcases the involvement of two ciliated neuron-intestine axes in this nematode to facilitate differential response to pathogenic microbes.…”

Section: Discussionmentioning

confidence: 60%

“…OSM-6 regulated immune effectors CLEC-60 is a C type lectin. It is under the control of wnt pathway in S. aureus infection (Labed et al, 2018). Wnt pathway function in E. faecalis infection and its control by ciliated neurons would be an interesting question to be pursued in future.…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis eleganssensory neurons modulate pathogen specific responses via HLH-30/TFEB transcription factor and FSHR-1 GPCR axes of immunity

Gupta

Varma

Singh

2019

Preprint

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Immune Resistance Immune Tolerance SENSORY NEURON INTESTINAL EPITHELIUM E. faecalis P. aeruginosa GRAPHICAL ABSTRACT 2 Caenorhabditis elegans sensory neurons modulate pathogen specific responses via HLH-30/TFEB transcription factor and FSHR-1 GPCR axes of immunity ABSTRACT Pattern recognition receptors allow animals to sense microbe associated molecular patterns and mount effective immune responses. It is not clear how Caenorhabditis elegans recognizes pathogenic microbes in absence of classical pattern recognition pathways. Here, we asked if sensory neurons of C. elegans allow it to distinguish between pathogens. Exposure of C. elegans to a Gram positive bacteriumEnterococcus faecalis or to a Gram negative bacterium Pseudomonas aeruginosa showed predominantly pathogen-specific signatures. Using nematodes defective in sensory perception, we show that neuronal sensing is essential to mount pathogen specific immune response. OSM-6 expressing, ciliated neurons exert non-cell autonomous control of immune effector production via an OSM-6-FSHR-1 GPCR axis as well as an OSM-6-HLH-30/TFEB transcription factor axis during E. faecalis infection. OSM-6-FSHR-1 axis also controls immune response to P. aeruginosa. In all, this study delineates essential role of sensory perception in the regulation of pathogenspecific immunity in C. elegans.

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“…Thus, although no intestinal GABAergic cells were reported, GABA could be pleiotropically sensed by a number of cells. In an infection model, Staphylococcus aureus molecules can trigger neuroendocrine reactions in C. elegans [42]. In our work, by using systemic and TRN specific reverse genetics, we show that systemically delivered dsRNA of unc-47, lgc-37 and gab-1 decreases neuroprotection in HT115 bacteria.…”

Section: Bacterial Gaba Is Neuroprotectivementioning

confidence: 59%

Bacterially produced GABA protects neurons from degeneration

Urrutia

García

Fuentes-Flores

et al. 2019

Preprint

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Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the MEC-4(d) DEG/ENaC channel which causes the progressive degeneration of the touch receptor neurons (TRNs). Using such model, this study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. While degeneration of TRNs was steadily carried and completed at adulthood in the strain routinely used for C. elegans maintenance Escherichia coli OP50, it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of the DAF-16/FOXO transcription factor, a phenomenon previously reported to underlie neuroprotection caused by downregulation of the insulin receptor in this system. Moreover, a daf-16 loss of function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics and metabolomics approaches pinpointed the neurotransmitter γ -aminobutyric acid (GABA) as a metabolite differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Together, these results demonstrate that bacterially produced GABA exerts an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.

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Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection

Cited by 69 publications

References 88 publications

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche

Caenorhabditis eleganssensory neurons modulate pathogen specific responses via HLH-30/TFEB transcription factor and FSHR-1 GPCR axes of immunity

Bacterially produced GABA protects neurons from degeneration

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