Abstract
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.
Keywords
- Crohn’s disease
- Infliximab
- Matrix metalloproteinase-2
- Matrix metalloproteinase-9
- Extracellular vesicles
- RAGE
- NLRP3 inflammasome
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This retrospective study was approved by Beijing Chao-yang Hospital Human Research Ethics Committee (Approval No. BJCY2025-331). The requirement for informed consent was waived by the Ethics Committee because of the retrospective nature of the study and the use of anonymous data. All procedures were performed in accordance with the ethical standards of the institutional research committee and with the Declaration of Helsinki.
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