Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways
Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W. Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L. Williams, Chuanfu Li, Laisel Martinez, Roberto I. Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W. Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L. Williams, Chuanfu Li, Laisel Martinez, Roberto I. Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
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Research Article Immunology Inflammation

Aorta- and liver-generated TMAO enhances trained immunity for increased inflammation via ER stress/mitochondrial ROS/glycolysis pathways

Abstract

We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in nonliver tissues and whether TMAO promotes inflammation via trained immunity (TI). We found that endoplasmic reticulum (ER) stress genes were coupregulated with MitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas; TMAO transdifferentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1. TMAO upregulated 3 mitochondrial genes, downregulated inflammation inhibitor DARS2, and induced mitoROS, and mitoTEMPO inhibited TMAO-induced ICAM-1. β-Glucan priming, followed by TMAO restimulation, upregulated TNF-α by inducing metabolic reprogramming, and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided potentially novel insights regarding TMAO roles in inducing EC activation and innate immune transdifferentiation and inducing metabolic reprogramming and TI for enhanced vascular inflammation, and they have provided new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammation, transplantation, aging, and cancer.

Authors

Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W. Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L. Williams, Chuanfu Li, Laisel Martinez, Roberto I. Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, Xiaofeng Yang

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Figure 3

Extrahepatic expression of FMO3.

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Extrahepatic expression of FMO3. scRNA-Seq data show that flavin-contain...
scRNA-Seq data show that flavin-containing dimethylaniline monooxygenase 3 (FMO3) was expressed in the human aortic cells and aorta cells from mice fed with HFD, and aorta of WT and ApoE–/– mice. (A) Single-cell transcriptome analysis of the ascending aortas of HFD-fed mice identified 10 cell types including ECs, fibroblasts, SMCs, B cells, T cells, macrophages, DCs, mesothelial cells, pericytes, and neural cells. (B) FMO3 expression in the aortic cells of HFD-fed mice. (C) Single-cell transcriptome analysis showed 12 cell types identified in the human thoracic aorta. (D) FMO3 expression in the human aortic cells. The data mining analyses were performed on the scRNA-Seq database of the Broad Institute of MIT and Harvard. (E) Real-time PCR showed the FMO3 expression in the aorta and liver of WT and ApoE–/– mice (n = 3 samples in each group and each sample containing aortas and liver from 2 mice). (F) Schematic diagram showing the TMAO biogenesis under physiological conditions in liver tissue; however, the pathological conditions transform the aorta into TMAO-generating tissue (t test; *P < 0.05).