Immune defenses in the urinary tract

Abstract

Recent advances in preclinical modeling of urinary tract infections (UTIs) have enabled the identification of key facets of the host response that influence pathogen clearance and tissue damage. Here, we review new insights into the functions of neutrophils, macrophages, and antimicrobial peptides in innate control of uropathogens and in mammalian infection-related tissue injury and repair. We also discuss novel functions for renal epithelial cells in innate antimicrobial defense. In addition, epigenetic modifications during bacterial cystitis have been implicated in bladder remodeling, conveying susceptibility to recurrent UTI. In total, contemporary work in this arena has better defined host processes that shape UTI susceptibility and severity and might inform the development of novel preventive and therapeutic approaches for acute and recurrent UTI.

Keywords: Escherichia coli; antimicrobial peptides; epigenetic remodeling; innate immunity; macrophages; neutrophils; pyelonephritis.

Figure 1.. Recent findings illuminating immune responses to UPEC in the murine kidney and urinary bladder.

In the murine kidney, UPEC adhere to mannosylated proteins in the renal collecting duct, forming kidney intracellular communities (KBCs) in the tubular lumen [13,48]. Inhibition of PAD4 in mice reduced neutrophil NET production and increased UPEC titer [8,12]. Depletion of neutrophils, deletion of TLR4, or exposure to testosterone favored severe infection and abscess formation in mice [,,–17]. Monocyte depletion in the kidney reduced cytokine concentrations and renal scarring in pyelonephritis [17], while the addition of testosterone induced “M2a-like” macrophage polarization and increased scarring [19]. Reduced IL-17 secretion in the urinary tract, through genetic deletion or the addition of testosterone, increased the propensity for chronic UTI in mice [2,37]. In the human and murine bladder, UPEC are known to invade umbrella cells, forming intracellular bacterial communities (IBCs), while a small proportion of UPEC form quiescent intracellular reservoirs (QIRs) within endosomes in these cells [78,79]. In the murine bladder, tissue-resident MacM and MacL macrophages have differentially responded to UPEC, participating in antigen presentation (MacM) and UPEC phagocytosis (MacL) [29]. Stimulation of a T_H2 response by mast cell-secreted IL-10 increased bacterial load [32,33], while stimulation of a T_H1 cellular response through a vaccine adjuvant increased IFNγ production, promoting UPEC clearance from the bladder relative to controls [32]. Tissue-resident memory (T_RM) cells arising after an initial episode of murine cystitis contributed to the control of bacterial loads upon reinfection [39]. Figure created with Biorender.com

Figure 2.. Epithelial responses to UPEC in the collecting duct.

During pyelonephritis, robust recruitment of neutrophils to the kidney leads to the formation of neutrophilic casts, a marker of acute pyelonephritis in both mice and humans [–12]. Complement component C5a was shown to ligate C5aR2 on murine myeloid cells, triggering pro-inflammatory cytokine secretion and increasing propensity for epithelial injury and renal scarring, some of which may be driven by pro-fibrotic “M2a-like” macrophages [6,42]. C5a was also shown to act on C5aR1 on principal cells (PCs) in the collecting duct, increasing expression of cell-surface mannosylated proteins, thereby enhancing UPEC binding and kidney bacterial community (KBC) formation [40,41,48]. Sensing of UPEC by hybrid PC-ICs shifted their mRNA expression, adopting the behavior of phagocytic ICs, which kill UPEC within acidified lysosomes [51]. Secretion of antimicrobial peptides (AMPs) including RNase7, RNase4, and NGAL by ICs can protect the urinary tract via direct killing of uropathogens or by modulating inflammatory responses [,–66,71]. The AMP response is driven in part by insulin receptor signaling, which is dampened in type 2 diabetes (diabetes mellitus). Figure created with Biorender.com