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Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

ABSTRACT: The signaling networks regulating antimicrobial activity during urinary tract infection (UTI) are incompletely understood. Interleukin-6 (IL-6) levels increase with UTI severity, but the specific contributions of IL-6 to host immunity against bacterial uropathogens are unknown. To clarify this we tested whether IL-6 activates the Stat3 transcription factor, to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI. Transurethral inoculation of uropathogenic Escherichia coli led to IL-6 secretion, urothelial Stat3 phosphorylation, and activation of antimicrobial peptide transcription, in a Toll-like receptor 4-dependent manner in a murine model of cystitis. Recombinant IL-6 elicited Stat3 phosphorylation in primary urothelial cells in vitro, and systemic IL-6 administration promoted urothelial Stat3 phosphorylation and antimicrobial peptide expression in vivo. IL-6 deficiency led to decreased urothelial Stat3 phosphorylation and antimicrobial peptide mRNA expression following UTI, a finding mirrored by conditional Stat3 deletion. Deficiency in IL-6 or Stat3 was associated with increased formation of intracellular bacterial communities, and exogenous IL-6 reversed this phenotype in IL-6 knockout mice. Moreover, chronic IL-6 depletion led to increased renal bacterial burden and severe pyelonephritis in C3H/HeOuJ mice. Thus, IL-6/Stat3 signaling drives a transcriptional program of antimicrobial gene expression in infected urothelium, with key roles in limiting epithelial invasion and ascending infection.

SUBMITTER: Ching CB

PROVIDER: S-EPMC5967986 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

Ching Christina B CB Gupta Sudipti S Li Birong B Cortado Hanna H Mayne Nicholas N Jackson Ashley R AR McHugh Kirk M KM Becknell Brian B

Kidney international 20180221 6

The signaling networks regulating antimicrobial activity during urinary tract infection (UTI) are incompletely understood. Interleukin-6 (IL-6) levels increase with UTI severity, but the specific contributions of IL-6 to host immunity against bacterial uropathogens are unknown. To clarify this we tested whether IL-6 activates the Stat3 transcription factor, to drive a program of antimicrobial peptide gene expression in infected urothelium during UTI. Transurethral inoculation of uropathogenic Es ...[more]

PMID: 29475562

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Project description:UnlabelledSignal transduction via MyD88, an adaptor protein engaged by the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) family receptors, has a crucial role in host defenses against group B streptococcus (GBS). To examine the contribution of IL-1R signaling to MyD88-dependent host defenses, we analyzed GBS infection in type I IL-1R (IL-1RI)-deficient mice. Most of these animals displayed clinical signs of sepsis and neurological disease and died after a challenge with a bacterial dose that did not cause illness or death in any of the wild-type animals. Moreover, bacterial numbers in the blood and brains of the immunodefective mice were considerably increased. The ability of blood leukocytes or bone marrow-derived macrophages to kill GBS in vitro was not affected by a lack of IL-1RI. However, it was found in a newly developed model of GBS-induced peritoneal inflammation that IL-1 signaling selectively promoted the production of the chemokines KC and MIP-1α and neutrophil recruitment. Moreover, the secretion of KC and MIP-1α, but not tumor necrosis factor alpha, by peritoneal macrophages stimulated with GBS was significantly decreased in the absence of IL-1RI. Accordingly, the number of neutrophils in the blood and the concentration of myeloperoxidase, a neutrophil marker, in infected organs were severely reduced in the immunodefective mice during GBS disease, concomitantly with a reduction in tissue KC and MIP-1α levels. In conclusion, IL-1RI plays a crucial role in host defenses against GBS by inducing the high-level production of chemokines and the subsequent recruitment of neutrophilic polymorphonuclear leukocytes to infection sites.ImportanceGroup B streptococcus (GBS) is a serious and frequent human pathogen. Experimental infection with this bacterium has been widely used to understand the mechanism whereby the body's first line of defense, represented by cells and molecules of the innate immune system, fights infections. In both humans and mice, defective function of the adaptor molecule MyD88 has been associated with extreme susceptibility to infection by GBS and other extracellular bacteria. We show here that lack of signaling by interleukin-1 (IL-1) cytokines can largely, although not completely, explain the increased susceptibility to infection observed in the absence of MyD88 function. We show, in particular, that IL-1 signaling through the IL-1 receptor promotes the production of the leukocyte attractant chemokines KC and MIP-1α and recruitment of neutrophils to GBS infection sites, thereby enabling these leukocytes to clear the infection. Our findings indicate that stimulation of IL-1 signaling may be useful as an alternative therapeutic strategy to treat GBS infections.

Project description:BackgroundUrinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI.MethodsC57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR.ResultsCompared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001).ConclusionsThese data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.

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Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

Publications

Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection.

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