Innate immunity and urinary tract infection

Abstract

Urinary tract infections are a severe public health problem. The emergence and spread of antimicrobial resistance among uropathogens threaten to further compromise the quality of life and health of people who develop acute and recurrent upper and lower urinary tract infections. The host defense mechanisms that prevent invasive bacterial infection are not entirely delineated. However, recent evidence suggests that versatile innate immune defenses play a key role in shielding the urinary tract from invading uropathogens. Over the last decade, considerable advances have been made in defining the innate mechanisms that maintain immune homeostasis in the kidney and urinary tract. When these innate defenses are compromised or dysregulated, pathogen susceptibility increases. The objective of this review is to provide an overview of how basic science discoveries are elucidating essential innate host defenses in the kidney and urinary tract. In doing so, we highlight how these findings may ultimately translate into the clinic as new biomarkers or therapies for urinary tract infection.

Keywords: Antimicrobial peptides; Cytokines; Innate immunity; Pattern recognition receptors; Pyelonephritis; Urinary tract infection.

Figure 1.

TLR4 signaling cascade. TLR4 activation by Lps requires co-receptors CD14 and MD2. Signaling cascades are MyD88-dependent (via NF-κB) and MyD88-independent (via IRF-3 and IRF-7) and result in interferon, cytokine, antimicrobial peptide (AMP), and inflammasome expression.

Figure 2.

Urothelial innate immunity. Bacteria bind to TLRs and form intracellular bacterial communities. UTI induces urothelial expression of the cytokine IL-6, which is involved in AMP expression, and the chemokine IL-8, which initiates neutrophil trafficking into the urinary space. Cell surface receptors CXCR1 and CXCR2 are expressed on urothelial cells to enhance neutrophil migration

Figure 3.

Leukocyte-epithelial cell interactions orchestrate the innate immune response to UPEC (A) Tubular cells establish the medullary Na+ gradient and secrete the chemokine Ccl2 in a NFAT5 dependent manner. [57] Ccl2 recruits circulating monocytes, which differentiate into macrophages These macrophages increase phagocytosis, IL-8 dependent neutrophil recruitment, and antimicrobial activity in the presence of sodium. This network of myeloid cells serves a critical role in limiting interstitial spread of bacteria. (B) Urothelial cells express TLR4 that recognizes bacterial LPS, resulting in production of IL-8 that elicits neutrophil chemotaxis. Efficient neutrophil transepithelial migration relies on resident macrophages, which recruit circulating monocytes in a Ccl2-dependent manner. Monocyte TNF-α stimulates macrophages to secrete Cxcl2. Cxcl2 stimulates neutrophil production of Mmp9, which degrades matrix and promotes efficient transepithelial neutrophil migration to the urinary space.[37, 60]