ArticleJournal of translational medicine2025
TREM1 facilitates nonresponse to anti-TNF-α monoclonal antibodies in colitis via boosting ITCH/TAK1/caspase-8 axis-mediated macrophage pyroptosis.
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Transforming growth factor β-activated kinase 1 as a central integrator of immune-microbiota crosstalk in colitis (Review).Experimental and therapeutic medicine · 2026Review
- Macrophage pyroptosis in inflammatory bowel disease: mechanistic insights, pathological roles and treatment strategies.Frontiers in immunology · 2026Review
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6 authors.
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Abstract
backgroundThe lack of response to TNF-α (tumor necrosis factor-alpha) monoclonal antibodies (mAbs) in autoimmune disease poses a considerable clinical challenge. Trigger receptor expressed on myeloid cells 1 (TREM1) has been proposed as a predictor of anti-TNF-α mAb responsiveness in inflammatory bowel disease (IBD), although this remains controversial. We investigated the role of TREM1 in nonresponders to infliximab (IFX) and elucidated the underlying mechanisms using experimental colitis models and macrophages.
methodsBioinformatics analysis of GEO datasets was used to evaluate the correlations between TREM1 -positive cell characteristics and IFX response. DSS-induced murine colitis models with AAV-mediated TREM1 overexpression were used to assess the therapeutic efficacy of TREM1 on IFX. TNF-α/IFX-treated TREM1-overexpressing THP-1 cells undergoing pyroptosis were observed through the scanning electron microscopy, LDH release assays and flow cytometry. R406 inhibition and ITCH shRNA were used to confirm the specific roles of p-SYK and ITCH in TREM1-triggered macrophage pyroptosis. Site-directed mutagenesis (Tyr344/620/737/772) revealed SYK-mediated ITCH phosphorylation at Tyr772.
resultsElevated intestinal TREM1 levels correlated with an inferior IFX response in IBD patients. Although IFX alleviated colitis in DSS-induced mice, its efficacy diminished following macrophage depletion, indicating that IFX relies on macrophages for its action. TREM1-overexpressing mice with colitis respond inadequately to IFX treatment, resulting in exacerbated pathological outcomes. In vitro, capase-8-dependent macrophage pyroptosis and insufficient therapeutic effects of IFX were observed in TREM1-overexpressing macrophages under TNF-α stimulation. Mechanistically, TREM1 overexpression downregulated TAK1 through activation of the E3 ubiquitin ligase ITCH in a DAP12/SYK-dependent manner. Activated SYK phosphorylates ITCH at Tyr772, enhancing its E3 ligase activity to promote TAK1 ubiquitination. R406-mediated p-SYK inhibition restored TAK1 levels by reducing ITCH phosphorylation, whereas the Tyr772 mutation attenuated both TAK1 degradation and macrophage pyroptosis.
conclusionsTREM1 diminishes the efficacy of IFX in IBD by promoting caspase-8-dependent macrophage pyroptosis through the p-SYK/ITCH/TAK1 axis. Therefore, targeting TREM1 and macrophage pyroptosis may provide new therapeutic strategies for IBD nonresponders to anti-TNF-α mAbs.
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