Toll-like receptor 4 modulates small intestine neuromuscular function through nitrergic and purinergic pathways

Valentina Caputi, Ilaria Marsilio, Silvia Cerantola, Mona Roozfarakh, Isabella Lante, Francesca Galuppini, Massimo Rugge, Eleonora Napoli, Cecilia R Giulivi, Genny Orso, Maria Cecilia Giron

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number350
JournalFrontiers in Pharmacology
Volume8
Issue numberJUN
DOIs
StatePublished - Jun 8 2017

Fingerprint

Enteric Nervous System
Toll-Like Receptor 4
Gastrointestinal Transit
Small Intestine
Neurons
Synaptic Transmission
Neuroglia
Purinergic P2Y1 Receptors
Dysbiosis
Purinergic P2X7 Receptors
Myenteric Plexus
Gliosis
Time and Motion Studies
Toll-Like Receptors
Inbred C57BL Mouse
Cholinergic Agents
Colon
Adenosine Triphosphate
Immunohistochemistry

Keywords

  • Enteric nervous system
  • Gut microbiota
  • Innate immunity
  • Intestinal motility
  • Intestinal transit
  • Knockout mice
  • Small bowel
  • Toll-like receptor 4

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Caputi, V., Marsilio, I., Cerantola, S., Roozfarakh, M., Lante, I., Galuppini, F., ... Giron, M. C. (2017). Toll-like receptor 4 modulates small intestine neuromuscular function through nitrergic and purinergic pathways. Frontiers in Pharmacology, 8(JUN), [350]. https://doi.org/10.3389/fphar.2017.00350

Toll-like receptor 4 modulates small intestine neuromuscular function through nitrergic and purinergic pathways. / Caputi, Valentina; Marsilio, Ilaria; Cerantola, Silvia; Roozfarakh, Mona; Lante, Isabella; Galuppini, Francesca; Rugge, Massimo; Napoli, Eleonora; Giulivi, Cecilia R; Orso, Genny; Giron, Maria Cecilia.

In: Frontiers in Pharmacology, Vol. 8, No. JUN, 350, 08.06.2017.

Research output: Contribution to journalArticle

Caputi, V, Marsilio, I, Cerantola, S, Roozfarakh, M, Lante, I, Galuppini, F, Rugge, M, Napoli, E, Giulivi, CR, Orso, G & Giron, MC 2017, 'Toll-like receptor 4 modulates small intestine neuromuscular function through nitrergic and purinergic pathways', Frontiers in Pharmacology, vol. 8, no. JUN, 350. https://doi.org/10.3389/fphar.2017.00350
Caputi, Valentina ; Marsilio, Ilaria ; Cerantola, Silvia ; Roozfarakh, Mona ; Lante, Isabella ; Galuppini, Francesca ; Rugge, Massimo ; Napoli, Eleonora ; Giulivi, Cecilia R ; Orso, Genny ; Giron, Maria Cecilia. / Toll-like receptor 4 modulates small intestine neuromuscular function through nitrergic and purinergic pathways. In: Frontiers in Pharmacology. 2017 ; Vol. 8, No. JUN.
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AU - Caputi, Valentina

AU - Marsilio, Ilaria

AU - Cerantola, Silvia

AU - Roozfarakh, Mona

AU - Lante, Isabella

AU - Galuppini, Francesca

AU - Rugge, Massimo

AU - Napoli, Eleonora

AU - Giulivi, Cecilia R

AU - Orso, Genny

AU - Giron, Maria Cecilia

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AB - 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.

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