Infliximab treatment affects serological expression of matrix metalloproteinases MMP-2 and -9 in Crohn's disease via extracellular vesicle-derived RAGE via the NLRP3 pathway

Background Matrix metalloproteinases MMP-2 and MMP-9 contribute to tissue remodeling and barrier dysfunction in Crohn’s disease (CD). Although infliximab modulates their serological levels, the underlying mechanisms remain unclear. This study investigated whether infliximab regulates serum MMP-2 and MMP-9 expression through extracellular vesicle (EV)-derived receptor for advanced glycation end-products (RAGE) and the NLRP3 inflammasome pathway. Methods Forty-two patients with active CD receiving infliximab induction therapy and 20 healthy controls were enrolled. Serum MMP-2 and MMP-9 levels were measured by ELISA at baseline and weeks 2, 6, and 14. Circulating EVs were isolated and characterized, and EV-associated RAGE was quantified. NLRP3 inflammasome activation was assessed in peripheral blood mononuclear cells (PBMCs). In vitro, healthy donor PBMCs were stimulated with patient-derived EVs in the presence or absence of a RAGE-blocking antibody or the NLRP3 inhibitor MCC950. Results Infliximab treatment significantly decreased serum MMP-9 levels (more markedly in clinical responders) while modestly increasing MMP-2 levels. EV-RAGE content was elevated in active CD and declined after infliximab, correlating positively with serum MMP-9. Infliximab also suppressed NLRP3 and cleaved caspase-1 expression as well as serum IL-1β. Patient-derived EVs induced NLRP3 activation, IL-1β secretion, and MMP-9 release in healthy PBMCs; these effects were attenuated by RAGE blockade or MCC950. Conclusion: Infliximab modulates serological MMP-2 and MMP-9 expression in Crohn’s disease, at least partly by reducing EV-derived RAGE and thereby inhibiting NLRP3 inflammasome-driven MMP-9 production. The EV-RAGE–NLRP3 axis may represent a novel mechanism and potential biomarker of anti-TNF therapeutic effects on matrix remodeling in CD. Conclusions Infliximab treatment modulates serological MMP-2 and MMP-9 expression in Crohn’s disease through an extracellular vesicle-derived RAGE–NLRP3 pathway. Reduction of EV-associated RAGE suppresses NLRP3 inflammasome activation, leading to decreased MMP-9 production. This mechanism offers new insight into the tissue-remodeling effects of anti-TNF therapy and identifies a potential target for optimizing treatment strategies in Crohn’s disease.