Abstract 642: Caspase-4/11 Promotes A High-fat Diet And Chronic Kidney Disease-accelerated Vascular Inflammation Via Novel Caspase-4/11-il-1b Two-step Trained Immunity

Abstract

To determine whether hyperlipidemia and chronic kidney disease (CKD) have a synergy in accelerating vascular inflammation via a new trained immunity (TI, innate immune memory) mechanism, we performed aortic pathological analysis and RNA-sequencing in gene deficient mice. The following findings are made: 1) High fat diet feeding (HFD) in combination with 5/6 nephrectomy CKD (HFD-CKD) increases plasma LDL-VLDL levels, aortic cytosolic lipopolysaccharide (LPS) levels and caspase-11 activation in aorta, and upregulates 998 genes in TI pathways in aorta; 2) Caspase-11 deficiency decreases aortic neointimal hyperplasia, recruitments of monocytes and macrophages into aorta, and secretion of caspase-11-gasdermin D (GSDMD) secretome cytokine CCL22 in plasma; 3) Caspase-11 KO decreases N-terminal GSDMD membrane expression on mouse aortic CD45 - CD31 + endothelial cells (ECs) and reduces mouse aortic IL-1β levels; 4) LPS transfection into human aortic endothelial cells (HAECs) results in caspase-4 activation and increases N-terminal GSDMD membrane expression; 5) Endogenous proinflammatory palmitic acid activates caspase-4 and increases N-terminal GSDMD membrane expression in HAECs, and palmitic acid in combination with uremic toxin indoxyl sulfate and LPS transfection upregulates vascular cell adhesion molecule-1 (VCAM-1) expression; 6) LPS transfection increases mitochondrial reactive oxygen species (mitoROS); mitoROS inhibitor mito-TEMPO inhibits caspase-4 activation, N-terminal GSDMD membrane expression and VCAM-1 upregulation in HAECs; and 7) IL-1β serves as the second step and positive feedback of HFD-CKD promoted TI, promotes TI gene expression, enhances caspase-4-induced VCAM-1 expression and IL1β secretion in HAECs. Our results have provided novel insights over hyperlipidemia and CKD in accelerating vascular inflammation via novel two step trained immunity mechanism and new therapeutic targets for treating chronic kidney disease, Gram-negative bacterial infections, cardiovascular diseases, inflammations, immune diseases, transplantation, aging and cancers.