Androgen exposure alters the neutrophil response to pyelonephritis

Abstract Urinary tract infections (UTIs) in men are uncommon but carry increased risk for severe upper-tract UTI (pyelonephritis) and complications including renal scarring. In preclinical models of Escherichia coli UTI, male C3H/HeN mice uniformly develop high-titer pyelonephritis (most with renal abscesses), while the majority of female C3H/HeN mice resolve renal infection within 7–14 days. We previously showed that this difference in outcomes is testosterone dependent. Here, we find that androgen exposure in female C3H/HeN mice alters the neutrophil response to UTI, increasing the propensity for severe renal inflammation and abscess formation as opposed to bacterial clearance and resolution of infection. Concordant with our prior published results, androgen exposure in C3H female mice given Escherichia coli UTI led to 3-log higher bacterial loads in the kidneys by 14 days post infection. We found that the kidneys of androgen-exposed mice harbored more neutrophils than standard females at baseline and throughout infection, correlated with higher levels of the neutrophil-recruiting chemokine CXCL1 (murine KC) in kidney tissue. In addition, the kidneys of androgen-exposed females were enriched for aged, immature neutrophils (Ly6G+, CD49d+, CD101−). Compared to their mature (CD101+) counterparts, these cells exhibited markers of increased degranulation, altered phagocytic activity, and diminished capacity for efflux from kidney tissue. These data support a model in which androgen-exposed mice, despite an apparently more robust neutrophil presence, fail to control renal bacterial infection due to altered neutrophil functions. Supported by grants from NIH (R01 DK111541, R01 DK126697, R01 AI158418)