The catheterized bladder environment induces dysregulation of macrophage polarization exacerbating bacterial UTI.

Urinary catheterization causes bladder damage, predisposing hosts to catheter-associated urinary tract infections (CAUTIs). CAUTI pathogenesis is mediated by bladder damage-induced inflammation, resulting in accumulation and deposition of the blood-clotting protein fibrinogen (Fg) and its matrix form fibrin, which are exploited by uropathogens as biofilm platforms to establish infection. Catheter-induced inflammation also results in robust immune cell recruitment, including macrophages (Mϕs). A fundamental knowledge gap is understanding the mechanisms by which the catheterized-bladder environment suppresses the Mϕ antimicrobial response, allowing uropathogen persistence. Here, we found that Fg and fibrin differentially modulate M1 and M2 Mϕ polarization, respectively. We unveiled that fibrin accumulation in catheterized mice induced an anti-inflammatory M2-like Mϕ phenotype, correlating with pathogen persistence. Even GM-CSF treatment of wildtype mice to promote M1 polarization was not sufficient to reduce bacterial burden and dissemination, indicating that the catheterized-bladder environment provides mixed signals, dysregulating Mϕ polarization, hindering its antimicrobial response against uropathogens.