Caspase-4/11 promotes hyperlipidemia and chronic kidney disease–accelerated vascular inflammation by enhancing trained immunity
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
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
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Research Article Inflammation Vascular biology

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

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

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Figure 5

Caspase-11 deficiency decreases the cleavage of N-GSDMD in the aortas of HFD+CKD mice.

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Caspase-11 deficiency decreases the cleavage of N-GSDMD in the aortas of...
(A) Five endothelial cell activation genes were identified in Venn diagram of 584 significantly downregulated genes in casp11–/– aortas and 1,311 endothelial cell activation genes identified in the literature (P < 0.05, log2FC < –1). (B and C) Intravital microscopy was used to examine peripheral blood cell rolling and adhesion in the cremaster muscle vein in male mice (n = 4–6). (D) Western blot analysis showed that HF+CKD increased the expression of endothelial cell adhesion molecule VCAM-1 in aortas compared with CKD and HFD-sham controls, suggesting that HFD+CKD activates aortic endothelial cells. (E) Flow cytometry gating analysis was used on mouse aorta cells to examine membrane GSDMD expression (n = 3–4). (F) Quantification of N-GSDMD expression was performed in endothelial cells (CD45–CD31+) in WT and casp11–/– HFD+CKD and HFD-Sham mouse aortas. (G) IL-1β secretion in the aorta of WT and casp11–/– HFD+CKD and HFD-Sham mice were quantified by ELISA. The Mann Whitney U test was used in B and C. The Kruskal-Wallis test with Benjamini and Hochberg multiple-comparison method was used to control the overall FDR of 5% (F and G).