Macrophage Dysfunction in Diabetic Urinary Tract Infection
Diabetes is associated with an increased prevalence and severity of urinary tract infections (UTIs), however the mechanisms accounting for this complication remain elusive. Macrophages are cells of the innate immune system that orchestrate inflammatory and reparative responses. Evidence is emerging that macrophage dysfunction in diabetes contributes to inflammatory complications of this disease. While the mechanisms of macrophage dysfunction in diabetes are not well understood, it is likely that the underlying metabolic abnormalities are important contributors. In diabetes, elevated circulating lipids increase the delivery of fatty acids to non-adipose cells, including macrophages, in which they impair cellular function. In response to bacteria, macrophages upregulate acyl-CoA synthetase 1 (ACSL1), a lipid metabolic enzyme that regulates the partitioning of fatty acids within cells. In other cell types such as cardiomyocytes and hepatocytes, upregulation of ACSL1 promotes lipid toxicity when elevated concentrations of fatty acids are present. Based on these findings, the central hypothesis of this proposal is that increased expression of ACSL1 in macrophages during a UTI will render these cells particularly susceptible to the toxic effects of the excess lipids present in diabetes. The main objective of this proposal is to determine how the lipid metabolic program directed ACSL1 modulates macrophage lipotoxicity and influences the pathogenesis of a UTI. Our preliminary studies demonstrate that ACSL1 deficiency in macrophages reduces cell death and diminishes release of the inflammasome regulated cytokine IL-1ß in response to lipid-inflammatory stress. We predict that bacterial clearance, resolution of inflammation, and bladder regeneration will be impaired in diabetic hosts following infection with uropathogenic E. coli (UPEC). In Aim 1, the interaction between ACSL1 and fatty acid excess will be investigated using an ex vivo infection system. Disease relevant outputs including bacterial titer, inflammasome activation, and macrophage cell death will be assessed. Aim 2 will translate these findings to an in vivo model of UTI. For these studies, mice lacking ACSL1 in the myeloid compartment will be rendered diabetic by high fat diet feeding and then infected with UPEC. Metrics of bacterial clearance, inflammation, and bladder regeneration will be determined. The proposed studies will elucidate novel molecular targets downstream of ACSL1 that alter crosstalk between fatty acids and macrophage responses to inflammation. This work is an important first step in the investigation of how macrophage dysfunction contributes to UTI pathogenesis in diabetes. The outcomes of this research will provide important evidence that macrophage metabolic pathways may be a viable target for therapy in the treatment of inflammatory and infectious diabetes complications.

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