The Humoral Pattern Recognition Molecule PTX3 Is a Key Component of Innate Immunity against Urinary Tract Infection

Abstract

Immunity in the urinary tract has distinct and poorly understood pathophysiological characteristics and urinary tract infections (UTIs) are important causes of morbidity and mortality. We investigated the role of the soluble pattern recognition molecule pentraxin 3 (PTX3), a key component of the humoral arm of innate immunity, in UTIs. PTX3-deficient mice showed defective control of UTIs and exacerbated inflammation. Expression of PTX3 was induced in uroepithelial cells by uropathogenic Escherichia coli (UPEC) in a Toll-like receptor 4 (TLR4)- and MyD88-dependent manner. PTX3 enhanced UPEC phagocytosis and phagosome maturation by neutrophils. PTX3 was detected in urine of UTI patients and amounts correlated with disease severity. In cohorts of UTI-prone patients, PTX3 gene polymorphisms correlated with susceptibility to acute pyelonephritis and cystitis. These results suggest that PTX3 is an essential component of innate resistance against UTIs. Thus, the cellular and humoral arms of innate immunity exert complementary functions in mediating resistance against UTIs.

The Long Pentraxin PTX3 as a Key Component of Humoral Innate Immunity and a Candidate Diagnostic for Inflammatory Diseases

“…In contrast, induction of PTX3 by LPS is amplified by IL-10 [42], suggesting that PTX3 may be involved in the IL-10-mediated regulation of inflammation. Accordingly, PTX3 deficiency has been associated with an increased inflammatory response and tissue damage in sterile or infectious conditions [43,44,45]. In addition, PTX3 is stored in neutrophil-specific granules in a ready-to-use form and undergoes release in response to microorganisms or TLR agonists [46].…”

“…Given the abundance of neutrophils in the circulation, neutrophil-associated PTX3 represents a major source of PTX3 covering a temporal window preceding gene-expression-dependent production [46]. Most recently, we reported the expression of PTX3 in uroepithelial cells [43]. Expression increased rapidly upon the stimulation by uropathogenic Escherichia coli (UPEC) in a TLR4- and MyD88-dependent manner [43].…”

Kidney α–intercalated cells and lipocalin 2: defending the urinary tract

“…The observation by Paragas et al that LCN2 is not constitutively present in the urinary tract, but rather produced in direct proportion to the bacterial numbers in urine (7), is similar to other antimicrobial agents, including pentraxin-3 and HBD-1, that are also secreted in direct proportion to the size of the bacterial threat (10). As urine is a very rich medium and can be retained for many hours in the bladder, the urinary tract can serve as a powerful incubator for bacterial growth.…”

An acidic microenvironment sets the humoral pattern recognition molecule PTX3 in a tissue repair mode

“…In addition, an augmented content of factors (CD62P, TGF, PDGF, serotonin, CXCL1, and CXCL2) possibly derived from platelets PTX3 binds selected conserved microbial molecules and has antibody-like functions: it has opsonic activity via Fc receptors (Lu et al, 2008;Bottazzi et al, 2010), activates and regulates the complement cascade Ricklin and Lambris, 2013), and regulates inflammation Deban et al, 2010). Genetic evidence in mouse and man indicates that PTX3 is essential for resistance against selected pathogens, such as Aspergillus fumigatus, Pseudomonas aeruginosa, and Klebsiella pneumoniae (Garlanda et al, 2002;Bottazzi et al, 2010;Cunha et al, 2014;Jaillon et al, 2014), and plays a protective role in different conditions associated with tissue injury (Salio et al, 2008;Norata et al, 2009;Bottazzi et al, 2010;Deban et al, 2010).…”