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 1

IL1B is positively correlated with chronic kidney disease (CKD) progression.

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IL1B is positively correlated with chronic kidney disease (CKD) progres...
(A) The expression of IL1B was increased in the glomeruli of patients with CKD. (B) IL1B expression in kidneys was inversely correlated with glomerular filtration rates (GFR) (Pearson analysis). The data were extracted from human Glomeruli samples (199 samples) in the NephroSeq database. (C) High-fat diet-fed (HFD) 5/6 nephrectomy mouse model of CKD with sham controls and normal chow diet (ND) controls. (D and E) HFD resulted in hyperlipidemia/dyslipidemia but did not exacerbate IL1B levels in the kidney or impair kidney function. (D) Cholesterol levels in the plasma of HFD+CKD, HFD-sham, ND-CKD, and ND-sham mice (<100 was considered normal by The Jackson Laboratory). (E) LDL/VLDL levels in the plasma of HFD+CKD, HFD-sham, ND-CKD, and ND-sham mice (n = 3–4 per group). (F) Blood urea nitrogen (BUN) levels in the plasma of HFD+CKD, HFD-sham, ND-CKD, and ND-sham mice. BUN < 24 was considered normal based on Mayo Clinic criteria (n = 5 in ND-sham, n = 7 in ND-CKD and HFD-sham, n = 13 in HFD+CKD). (G) IL1B levels in the aorta of HFD+CKD, HFD-sham, ND-CKD, and ND-sham. Two-tailed Student’s t test was used in A; Pearson correlations were used in B. The Kruskal-Wallis test with Benjamini and Hochberg multiple-comparison method was used to control the overall FDR of 5% (D–G).