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Protective role of TRPM7 knockdown in ulcerative colitis via blocking NLRP3 inflammasome-mediated pyroptosis
Jinzhen Peng1, Shuai Tang1, Lifang Huang2
1Department of gastroenterology, Shaoguan First People's Hospital, Shaoguan 512000, PR China.
Abstract:
Transient receptor potential melastatin 7 (TRPM7) has been emerged as a potent drug target for immunomodulation with ion conductance and kinase activities. The research is projected to characterize the influences of TRPM7 on the course of ulcerative colitis (UC) and dissect the latent response mechanisms. The in vivo murine model and in vitro cell model of UC were both stimulated by DSS. RT-qPCR and western blotting tested the abundance of TRPM7. Colonic damage was estimated by Hematoxylin-eosin staining, calculation of colon length, measurement of DAI and MPO assay kit. CCK-8 method and TUNEL staining severally ascertained cell activity and apoptosis. ELISA method assayed the inflammatory levels and relevant assay kits determined oxidative stress levels. FITC-dextran flux, immunohistochemistry, TEER as well as western blotting evaluated intestinal barrier function. Immunofluorescence staining and western blotting appraised NLR family pyrin domain containing 3 (NLRP3)-dependent pyroptosis. Depleted TRPM7 retarded inflammation, oxidative damage as well as intestinal barrier damage both in vitro and in vivo. TRPM7 reduction repressed the pyroptosis mediated by NLRP3 inflammasome. NLRP3 agonist nigericin partly abolished the protection elicited by TRPM7 silencing against inflammation, oxidative damage as well as intestinal barrier damage in vitro. Collectively, TRPM7 deletion might possess the therapeutic potential in UC, the working mechanism of which might involve the inactivation of NLRP3-dependent pyroptosis.
Insights
Targeting TRPM7 (Transient Receptor Potential Melastatin 7) shows therapeutic potential for ulcerative colitis (UC). Reducing TRPM7 alleviates inflammation and gut barrier damage by inhibiting NLRP3-dependent pyroptosis.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Transient receptor potential melastatin 7 (TRPM7) exhibits ion channel and kinase functions, making it a potential target for immunomodulation.
- Ulcerative colitis (UC) is a chronic inflammatory bowel disease with complex underlying mechanisms.
Purpose of the Study:
- To investigate the role of TRPM7 in the pathogenesis of ulcerative colitis (UC).
- To elucidate the molecular mechanisms by which TRPM7 influences UC progression.
Main Methods:
- Established in vivo murine and in vitro cell models of UC using DSS stimulation.
- Assessed TRPM7 expression via RT-qPCR and Western blotting.
- Evaluated colonic damage, inflammation, oxidative stress, and intestinal barrier function using various assays (H&E, DAI, MPO, ELISA, FITC-dextran flux, TEER).
- Investigated NLRP3-dependent pyroptosis using immunofluorescence and Western blotting.
Main Results:
- TRPM7 depletion significantly reduced inflammation, oxidative damage, and intestinal barrier dysfunction in both in vitro and in vivo UC models.
- Silencing TRPM7 suppressed NLRP3 inflammasome-mediated pyroptosis.
- Administration of an NLRP3 agonist partially reversed the protective effects of TRPM7 silencing.
Conclusions:
- TRPM7 plays a crucial role in UC development.
- TRPM7 deletion demonstrates therapeutic potential for UC by inhibiting NLRP3-dependent pyroptosis.
- Targeting TRPM7 may offer a novel therapeutic strategy for managing ulcerative colitis.
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