Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells

Brun, Paola; Gobbo, Serena; Caputi, Valentina; Spagnol, Lisa; Schirato, Giulia; Pasqualin, Matteo; Levorato, Elia; Palù, Giorgio; Giron, Maria Cecilia; Castagliuolo, Ignazio

doi:10.1016/j.mcn.2015.03.018

Cited by 71 publications

(55 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among all TLRs, TLR4 is the best characterized pathogen-recognition receptor and recently recognized to modulate ENS phenotype and function (Anitha et al, 2012). We recently showed the expression of TLR4 mRNA transcripts in freshly isolated smooth muscle cells and enteric glial cells (EGCs) but not in resident macrophages and dendritic cells (Brun et al, 2015). In vivo , under steady-state conditions, TLR4 is generally absent or detected in very small amounts in intestinal epithelial cells and in immune cells located in the subepithelial lamina propria, in order to avoid inappropriate activation despite the omnipresent microbiota (Cario, 2010).…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

et al. 2017

Self Cite

View full text Add to dashboard Cite

Objective: Toll-like receptors (TLRs) play a pivotal role in the homeostatic microflora-host crosstalk. TLR4-mediated modulation of both motility and enteric neuronal survival has been reported mainly for colon with limited information on the role of TLR4 in tuning structural and functional integrity of enteric nervous system (ENS) and in controlling small bowel motility.Methods: Male TLR4 knockout (TLR4-/-, 9 ± 1 weeks old) and sex- and age-matched wild-type (WT) C57BL/6J mice were used for the experiments. Alterations in ENS morphology and neurochemical code were assessed by immunohistochemistry whereas neuromuscular function was evaluated by isometric mechanical activity of ileal preparations following receptor and non-receptor-mediated stimuli and by gastrointestinal transit.Results: The absence of TLR4 induced gliosis and reduced the total number of neurons, mainly nNOS+ neurons, in ileal myenteric plexus. Furthermore, a lower cholinergic excitatory response with an increased inhibitory neurotransmission was found together with a delayed gastrointestinal transit. These changes were dependent on increased ileal non-adrenergic non-cholinergic (NANC) relaxations mediated by a complex neuronal-glia signaling constituted by P2X7 and P2Y1 receptors, and NO produced by nNOS and iNOS.Conclusion: We provide novel evidence that TLR4 signaling is involved in the fine-tuning of P2 receptors controlling ileal contractility, ENS cell distribution, and inhibitory NANC neurotransmission via the combined action of NO and adenosine-5′-triphosphate (ATP). For the first time, this study implicates TLR4 at regulating the crosstalk between glia and neurons in small intestine and helps to define its role in gastrointestinal motor abnormalities during dysbiosis.

show abstract

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…The ENS defects in Tlr2 −/− mice, which lack GDNF, can be partially corrected by administration of exogenous GDNF or a TLR2 agonist [63]. Remarkably, intestinal smooth muscles, not glia, have been shown to be the main source of GDNF in mature mice [65]. …”

Section: Immune Regulation Of Ens Homeostasismentioning

confidence: 99%

Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract

Margolis

Gershon

Bogunovic

2016

Trends in Immunology

View full text Add to dashboard Cite

The gastrointestinal (GI) tract is the largest immune organ; in vertebrates, it is the only organ whose function is controlled by its own intrinsic enteric nervous system (ENS), but it is additionally regulated by extrinsic (sympathetic and parasympathetic) innervation. The GI nervous and immune systems are highly integrated in their common goal, which is to unite digestive functions with protection from ingested environmental threats. This review discusses the physiological relevance of enteric neuroimmune integration by summarizing the current knowledge of evolutionary and developmental pathways, cellular organization, and molecular mechanisms of neuroimmune interactions in health and disease.

show abstract

“…The mRNA encoding for TLRs have been detected on neurons[71], glial[72] and smooth muscle cells[73]. TLR-2 activation on smooth muscle leads to the production of neurotrophins that enhance the structural and functional integrity of the enteric nervous system[74]. …”

Section: Direct Effectsmentioning

confidence: 99%

Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota

Guarino¹,

Cicala²,

Putignani³

et al. 2016

WJG

View full text Add to dashboard Cite

Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro-intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro-intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll-like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios.

show abstract

Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells

Cited by 71 publications

References 49 publications

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

Toll-Like Receptor 4 Modulates Small Intestine Neuromuscular Function through Nitrergic and Purinergic Pathways

Cellular Organization of Neuroimmune Interactions in the Gastrointestinal Tract

Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota

Contact Info

Product

Resources

About