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| Autori principali: | , , , , , , , , , , , , |
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| Natura: | Artículo Open Access |
| Pubblicazione: |
Wiley
2025
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| Soggetti: | |
| Accesso online: | https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.17439 |
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- Toll‐like receptor 4 deficiency ameliorates experimental ileitis and enteric neuropathy: Involvement of nitrergic and 5‐hydroxytryptaminergic neurotransmission Sofia Faggin Silvia Cerantola Valentina Caputi Angela Tietto Elena Stocco Annalisa Bosi Alessandra Ponti Antonella Bertazzo Veronica Macchi Andrea Porzionato Edoardo V. Savarino Cristina Giaroni Maria Cecilia Giron British Journal of Pharmacology AbstractBackground and PurposeInflammatory bowel disease (IBD) patients display genetic polymorphisms in toll‐like receptor 4 (TLR4) genes, contributing to dysregulate enteric nervous system (ENS) circuits with increased levels of 5‐HT and alteration of the neuroimmune crosstalk. In this study, we investigated the impact of TLR4 signalling on mouse ENS dysfunction caused by dextran sulphate sodium (DSS)‐induced ileitis.Experimental ApproachMale C57BL/6J (wild‐type [WT]) and TLR4−/− mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and then were switched to 3‐day regular drinking water. Histological analysis and proinflammatory cytokine mRNA levels were assessed in ileal samples. Gut motility was evaluated by changes in transit of a fluorescent‐labelled marker and isometric neuromuscular responses of ileal full‐thickness segments to receptor and non‐receptor‐mediated stimuli. Alterations in ENS architecture were assessed by confocal immunohistochemistry in longitudinal muscle–myenteric plexus whole‐mount preparations.Key ResultsIn WT mice, DSS treatment caused delayed gastrointestinal transit, ileal myenteric neurodegeneration, reactive gliosis and release of proinflammatory cytokines. Enhanced cholinergic and tachykinergic excitatory tone, increased inducible nitric oxide synthase (iNOS)‐mediated relaxation, and changes in 5‐HT2A and 5‐HT3 receptor‐mediated responses were observed during ileitis in WT mice. TLR4 deficiency reversed most of the functional and morphological abnormalities.Conclusion and ImplicationsOur results demonstrate that TLR4 activity influences the severity of ileitis, neuroglial plasticity, gut motility, and nitrergic and 5‐HTergic neurotransmissions. The neuroimmune interaction between TLR4 and 5‐HT observed in our study appears to be a potential pharmacological target to treat ENS dysfunction implicated in IBD onset/progression. 10.1111/bph.17439 http://creativecommons.org/licenses/by/4.0/