British journal of pharmacology · 2025
Toll-like receptor 4 deficiency ameliorates experimental ileitis and enteric neuropathy: Involvement of nitrergic and 5-hydroxytryptaminergic neurotransmission.
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Faggin Sofia, Cerantola Silvia, Caputi Valentina, Tietto Angela, Stocco Elena, Bosi Annalisa, Ponti Alessandra, Bertazzo Antonella, Macchi Veronica, Porzionato Andrea, Savarino Edoardo V, Giaroni Cristina, Giron Maria Cecilia
Аннотация
BACKGROUND AND PURPOSE: Inflammatory 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 APPROACH: Male 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 RESULTS: In 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 IMPLICATIONS: Our 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.
EXPERIMENTAL APPROACH: Male 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 RESULTS: In 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 IMPLICATIONS: Our 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.