Abstract
BackgroundInflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders. S100A8/A9 promote endotoxin- and Escherichia (E.) coli-induced sepsis showing its contribution in systemic infection. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown.Methodology/Principal FindingsWe investigated the contribution of S100A8/A9 in acute urinary tract infection (UTI) by instilling 2 different doses of uropathogenic E. coli transurethrally in wild type (WT) and S100A9 knockout (KO) mice. Subsequently, we determined bacterial outgrowth, neutrophilic infiltrate and inflammatory mediators in bladder and kidney 24 and 48 hours later. UTI resulted in a substantial increase of S100A8/A9 protein in bladder and kidney tissue of WT mice. S100A9 KO mice displayed similar bacterial load in bladder or kidney homogenate compared to WT mice using 2 different doses at 2 different time points. S100A9 deficiency had little effect on the inflammatory responses to E. Coli-induced UTI infection, as assessed by myeloperoxidase activity in bladder and kidneys, histopathologic analysis, and renal and bladder cytokine concentrations.ConclusionsWe show that despite high S100A8/A9 expression in bladder and kidney tissue upon UTI, S100A8/A9 does not contribute to an effective host response against E. Coli in the urinary tract system.
Highlights
Most cases of ‘‘community-acquired’’ urinary tract infection (UTI) are due to enteric bacteria that enter the urinary tract, of which Escherichia (E.) coli is the most common organism (70–80%)
As shown in figure 1A–B, S100A8/A9 level was higher in bladder and kidney homogenates from wild type (WT) mice 24 and 48 hours after induction of UTI compared to sham mice
We performed double staining for Ly6G with S100A9 to study colocalization in kidney tissue slides obtained from WT mice, 24 hours after infection (Figure 1D–F)
Summary
Most cases of ‘‘community-acquired’’ urinary tract infection (UTI) are due to enteric bacteria that enter the urinary tract, of which Escherichia (E.) coli is the most common organism (70–80%). S100A8/A9 protein complex interacts with TLR4 [12] and the extent of S100A8/A9 expression correlates with disease activity in several inflammatory disorders [9,10,15,16]. It was shown that S100A9 KO mice were protected against mortality induced by endotoxic shock and E.coli induced sepsis suggesting a detrimental role during systemic inflammation and infection [12]. This shows the contribution of S100A8/A9 in systemic infection, its contribution in local infection is unknown. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown
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