Revealing How the Catheterized Bladder Environment Induces Anti-inflammatory Macrophage Polarization Resulting in Enhancing Bacterial Urinary Tract Infection

Despite short-term benefits, urinary catheterization predisposes patients to developing catheter-associated urinary tract infections (CAUTIs). Different from uncomplicated urinary tract infections, CAUTIs display unique clinical manifestations, diverse causative pathogens, and pathologic mechanisms. Catheter-induced tissue damage trigger fibrinogen (Fg) release into the bladder to form fibrin clots for tissue healing. However, Fg/fibrin accumulation within the bladder provided a scaffold for prevalent CAUTI pathogens, uropathogenic Escherichia coli (UPEC) and Enterococcus faecalis, to establish infection. Using a CAUTI mouse model, we observed that significant macrophage recruitment was ineffective at controlling infection. Importantly, our in vitro, ex vivo, and in vivo studies targeting specific coagulation factors unveiled that Fg or fibrin polarize macrophages to either pro- M1 or anti-inflammatory M2, respectively. Thus, we hypothesized that Fg and fibrin differentially polarizes macrophages: where Fg favors M1s to promote bactericidal response, while fibrin induces M2s to dampen antimicrobial activity. To investigate this, bladders of wildtype (WT) and coagulation-transgenic mice, such as mice with deficient soluble Fg (Fg-AEK; no coagulation) and plasminogen (Pg)-deficient mice (fibrin accumulation), were catheterized and infected with UPEC or E. faecalis for 24 hours. In catheterized Fg-AEK mice, we found higher presence of M1s with decreased bacterial burden. In contrast, catheterized Pg-deficient bladders exhibited higher M2s with increased bacterial burden. Thus, Fg promote M1s where it controls infection, while fibrin enhance M2s, suppressing pathogen control. Furthermore, co-injection with GM-CSF and IL-4 in WT mice with fibrin accumulation led to mixed polarization signals that increased presence of hybrid M1/M2 macrophages, which further exacerbated infection and dissemination by suppressing M1 antimicrobial response. Therefore, our studies demonstrated that the catheter-induced fibrin accumulation in the bladder impairs macrophages’ bactericidal response to active infection, thereby contributing to CAUTI pathogenesis. Thus, these findings will advance understanding CAUTI pathogenesis allowing us to develop future intervention strategies for catheterized patients.