Pyelonephritis decreases serum cholesterol and mitigates atherosclerosis severity despite systemic inflammation

Hypercholesterolemia and inflammation are main causes of cardiovascular disease. Urinary tract infections are common and frequently recur. We here tested how pyelonephritis affects atherosclerotic plaque development and lipid levels. LDL receptor-deficient (<i>Ldlr</i>^-/-) and wild-type mice were infected with uropathogenic <i>Escherichia coli</i>. Renal and systemic inflammation, lipid levels, and atherosclerotic plaque development were assessed. Gene regulation was studied in pyelonephritis and in human cells in vitro. In patients admitted with urinary tract infections, serum lipids and disease severity were studied. Chronic pyelonephritis increased spleen weight, caused anemia, neutrophilia, and systemically elevated proatherogenic cytokines. Atherosclerotic aortic root lesion size in <i>Ldlr</i>^-/- mice tended to be smaller. Decreased serum cholesterol positively associated with systemic neutrophil counts in wild-type and <i>Ldlr</i>^-/- mice with chronic pyelonephritis and negatively with <i>Ldlr</i>^-/- mice atherosclerotic lesion size. Cholesterol homeostasis and fatty acid metabolism related gene expression changes in the pyelonephritic kidney included known mediators of atherosclerosis, namely <i>Pcsk9</i>, <i>Lipa</i>, and <i>Stab2</i> downregulation and <i>Abca1</i> and <i>Msr1</i> upregulation. Magnitude of changes correlated with kidney neutrophil marker expression. Coincubation of human renal tubular epithelium or mononuclear cells with primary neutrophils under inflammatory conditions replicated <i>LIPA</i> and <i>MSR1</i> regulation. In patients admitted with urinary tract infections, leukocyte counts and inflammation markers C-reactive protein and procalcitonin negatively correlated with serum cholesterol. Our experiments demonstrate depression of serum cholesterol and relative protection against atherosclerotic lesion formation despite severe systemic inflammation in chronic bacterial kidney infection. They introduce regulation of renal cholesterol metabolism by neutrophils as an underlying mechanism.<b>NEW & NOTEWORTHY</b> Bacterial infections are common, and a risk factor for acute cardiovascular events. Chronic inflammation promotes atherosclerosis. However, in mice with chronic pyelonephritis and systemic inflammation and neutrophilia, atherosclerotic lesions were not enlarged. Rather, lesion size correlated with cholesterol levels that decreased significantly. A similar decrease of serum cholesterol with inflammation was found in patients admitted for urinary tract infections. These data support a clinical relevance of proatherogenic lipid decrease in severe bacterial infection.