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

Abstract

Background Infliximab is an effective biologic agent for Crohn’s disease (CD), but its precise mechanisms on matrix metalloproteinases (MMPs) and related pathways remain incompletely understood. This study aimed to investigate the effects of infliximab on serum MMP-2 and MMP-9 expression and to explore the mediating role of the NLRP3 inflammasome pathway via extracellular vesicle (EV)-derived RAGE. Methods A prospective cohort study was conducted at Beijing Chaoyang Hospital, Capital Medical University. Sixty-eight patients with active CD receiving infliximab therapy and 30 healthy controls were enrolled. Serum MMP-2 and MMP-9 levels, EV-derived RAGE expression, and NLRP3-related markers (IL-1β, IL-18, NLRP3, caspase-1) were measured at baseline and after treatment (weeks 6 and 30). In vitro experiments using patient-derived EVs on THP-1 macrophages and primary monocytes were performed to validate the mechanistic axis. Results Infliximab treatment significantly decreased serum MMP-9 and increased MMP-2 levels (P < 0.001). It also suppressed NLRP3 inflammasome activation and reduced EV-derived RAGE expression. EV-RAGE levels positively correlated with MMP-9 and NLRP3 activity. In vitro, pre-treatment EVs induced MMP-9 and IL-1β production in a RAGE- and NLRP3-dependent manner, while post-treatment EVs showed attenuated effects. Clinical responders exhibited more pronounced modulation of this axis. Conclusions Infliximab modulates the balance of MMP- 2 and MMP-9 in CD patients, at least partly through inhibition of the EV-derived RAGE/NLRP3 inflammasome pathway. Targeting this axis may provide new therapeutic strategies and biomarkers for personalized treatment in Crohn’s disease.