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 2

The expression and activity of caspase-4 are positively associated with the progression of CKD-accelerated vascular inflammation.

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The expression and activity of caspase-4 are positively associated with ...
(A) Casppase-1 (casp1) expression in the kidneys of patients with CKD compared with that of healthy donors. (B) Caspase-4 (CASP4) expression in the kidneys of patients with CKD compared with that of healthy donors. (C and D) CASP1 and CASP4 were negatively correlated with GFR (Pearson analysis). (E) The top 20 CASP4/Gasdermine D–related (GSDMD-related) secretion genes were significantly increased in patients with CKD (GSE66494). (F) The LPS level in the aorta of HFD+CKD, HFD-Sham, ND-CKD, and ND-Sham mice was detected by an ELISA kit (n = 4–6). (G) Casp11 activation scales in the HFD+CKD aorta were higher than those of CASP1. Western blot analysis of WT mouse aortic tissue for CASP1 and casp11. (H) Casp11 activities in the aorta of HFD+CKD, HFD-sham, ND-CKD, and ND-sham were detected by the casp4 activity assay. In total, 50 μg protein from each sample was used to detect casp11 activities (n = 4–6). (I) The proinflammatory cytokines in the plasma of HFD+CKD, HFD-sham, ND-CKD, and ND-sham were analyzed by cytokine array. Each sample was pooled from 3 mice in each group (n = 3). ImageJ was used to quantify the bands, and the significantly changed proteins were indicated. Two-tailed Student’s t test was used in A and B. Pearson correlations were used in C and D. The Kruskal-Wallis test with Benjamini and Hochberg multiple-comparison method was used to control the overall FDR of 5% (F, H, and I). *P < 0.05.