Fibrin-rich environment drives catheter-associated UTIs by suppressing macrophage defenses.

Catheter-associated urinary tract infections (CAUTIs) pose severe clinical challenges, often leading to urosepsis and multidrug resistance. The wound-healing process triggered by catheter-induced bladder damage deposits fibrinogen and its polymerized form, fibrin. However, uropathogens exploit the fibrinogen and fibrin matrix to form a protective biofilm. While catheter-induced inflammation recruits innate immune cells, particularly macrophages, to the site of infection, the persistence of uropathogens suggests that the local bladder environment alters their antimicrobial function. Our research pinpoints the coagulation cascade as a key driver of this dysfunction, finding a differential macrophage polarization influenced by fibrinogen and fibrin. We showed that urinary catheterization creates a fibrin-rich matrix that was correlated with polarizing macrophages into an anti-inflammatory M2-like state, suppressing their bactericidal response. In contrast, using mice expressing fibrinogen locked in the form of a monomer, we demonstrated that monomeric fibrinogen promotes a pro-inflammatory M1-like polarization state. Notably, skewing a M1-like macrophage state with GM-CSF failed to clear the infection and systemic dissemination, suggesting a dominant role for fibrin matrix in suppressing M1-like macrophage-mediated antimicrobial activity. Together, these findings show that the catheterized bladder provides signals that significantly alter macrophage function, creating an ideal niche for pathogen persistence.