Caspase-4/11 promotes hyperlipidemia and chronic kidney disease–accelerated vascular inflammation by enhancing trained immunity

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Abstract

To determine whether hyperlipidemia and chronic kidney disease (CKD) have a synergy in accelerating vascular inflammation via trained immunity (TI), we performed aortic pathological analysis and RNA-Seq of high-fat diet–fed (HFD-fed) 5/6 nephrectomy CKD (HFD+CKD) mice. We made the following findings: (a) HFD+CKD increased aortic cytosolic LPS levels, caspase-11 (CASP11) activation, and 998 gene expressions of TI pathways in the aorta (first-tier TI mechanism); (b) CASP11–/– decreased aortic neointima hyperplasia, aortic recruitment of macrophages, and casp11–gasdermin D–mediated cytokine secretion; (c) CASP11–/– decreased N-terminal gasdermin D (N-GSDMD) membrane expression on aortic endothelial cells and aortic IL-1B levels; (d) LPS transfection into human aortic endothelial cells resulted in CASP4 (human)/CASP11 (mouse) activation and increased N-GSDMD membrane expression; and (e) IL-1B served as the second-tier mechanism underlying HFD+CKD-promoted TI. Taken together, hyperlipidemia and CKD accelerated vascular inflammation by promoting 2-tier trained immunity.

Authors

Yu Sun, Yifan Lu, Lu Liu, Fatma Saaoud, Ying Shao, Keman Xu, Charles Drummer IV, Ramon Cueto, Huimin Shan, Xiaohua Jiang, Huaqing Zhao, Hong Wang, Xiaofeng Yang