Relaxation of mucosal fibronectin fibers in late gut inflammation following neutrophil infiltration in mice

Abstract

The continuously remodeled extracellular matrix (ECM) plays a pivotal role in gastrointestinal health and disease, yet its precise functions remain elusive. In this study, we employed laser capture microdissection combined with low-input proteomics to investigate ECM remodeling during Salmonella-driven inflammation. We also probed the mechanosensitive state of fibronectin, a crucial ECM component with diverse functions dependent on its tensile state. While fibronectin fibers in healthy intestinal tissue are typically stretched, we demonstrated their relaxation only hours after infection in intestinal smooth muscles, despite the absence of bacteria in that area. In contrast, within the mucosa, where Salmonella is present starting 12 hours post-infection, fibronectin fiber relaxation occured exclusively during late-stage infection at 72 hours, and was localized to neutrophil clusters. Using N-terminomics, we identified three new cleavage sites in fibronectin in the inflamed cecum. Our work suggests that the ECM remodeling responses of different tissue layers in the intestine are distinct and carefully orchestrated.