Marrufo, A. M.; Molina, J. J.; Gager, C.; Andersen, M. J.; La Bella, A. A.; Lucas, E.; Wongso, E.; Urmi, T.; Arias-Parbul, K.; Webster, R.; Stuckey, P. V.; Kohler, K. N.; Donahue, D.; Ploplis, V.; Flick, M. J.; Castellino, F. J.; Santiago-Tirado, F. H.; Flores-Mireles, A. L.

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. A fundamental knowledge gap is understanding the mechanisms by which the catheterized-bladder environment suppresses the macrophages; antimicrobial response, allowing uropathogen persistence. Here, we found that Fg and fibrin differentially modulate M1 and M2 macrophages; polarization, respectively. We unveiled that fibrin accumulation in catheterized mice induced an anti-inflammatory M2-like macrophages; 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 macrophages; polarization, hindering its antimicrobial response against uropathogens.