Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD

Abstract

We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid β-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.

Editorial: Endothelial cells as innate immune cells

“…However, immunological characters of endothelial cells have been poorly characterized due to the fact that endothelial cells have not been recognized as innate immune cells in the field. To fill in this significant knowledge gap, ten years ago based on more than ten major innate immune functional aspects that are shared by the prototypic innate immune cell type -macrophages and endothelial cells, we proposed a new concept that endothelial cells are innate immune cells (2,4), which was further supported by our experimental data (5)(6)(7)(8)(9)(10)(11)(12)(13) analyses (Shao et al,15). The Molecular Innate Immunity field is continuously evolving, and we greatly appreciate the Molecular Innate Immunity section editors gave us this opportunity to organize this Research Topic and work with other investigators to explore this important topic further.…”

“…Trained immunity is a novel mechanism for persistent hyperactivation and synergies between DAMPs/PAMPs One of the significant progresses in the innate immunity field is the identification of innate immune memory or trained immunity (15)(16)(17)(18). Ever since investigators found memory adaptive immune cells such as memory T cells and memory B cells, we have always been puzzled by two questions whether innate immune cells have memory functional status for challenged stimuli and whether innate immune cells have memory cell subtypes similar to that of adaptive immune cells.…”

“…16,28, Zhong et al). For current understanding, trained immunity(15,16, Zhong et al) is formed via metabolic reprogramming(29) and epigenetic memory(10,30, 31). All the cell types in aorta participate in this process including but not limited to endothelial cells, VSMCs(21, 32), monocytes, macrophages, neutrophils, T cells, CD4 + regulatory T cells (Treg) (33-37) (Ni et al; Shao et al; Xu et al, Zhang et al) and B cells.…”

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

“…This phenomenon is known as trained immunity or innate immune memory [ 59 , 80 ]. Trained immunity can occur in several traditional innate immune cells such as monocytes/macrophages, natural killer (NK) cells, dendritic cells (DCs), aortic cells, innate immune functions of T cells, and Treg cells, as well as in non-traditional immune cells such as vascular smooth muscle cells (VSMCs), endothelial cells (ECs), hepatocytes, and fibroblasts [ 59 , 81 , 82 , 83 , 84 , 85 ]. Trained immunity can be induced by several pathogen-associated molecular patterns (PAMPs)/danger-associated molecular patterns (DAMPs) stimuli such as lipopolysaccharides (LPS), β-glucan, Bacillus Calmette–Guerin (BCG), oxidized low-density lipoprotein (ox-LDL), and high-fat diet [ 86 , 87 , 88 , 89 ].…”

Editorial: Highlights for Cardiovascular Therapeutics in 2021 – Trained Immunity, Immunometabolism, Gender Differences of Cardiovascular Diseases, and Novel Targets of Cardiovascular Therapeutics

“…TI is important for host defense, vaccine response, and promoting the pathogenesis of chronic inflammations including metabolic CVDs such as atherosclerosis. In contrast to the memory function in the adaptive immune system with special cell subsets to carry out memory function such as memory T cells and memory B cells ( 22 ), TI can occur in innate immune cells such as monocytes/macrophages ( 23 ), natural killer cells, endothelial cells (ECs) ( 6 , 11 , 24 ), vascular smooth muscle cells ( 25 , 26 ), and nonimmune cells, such as fibroblasts ( 7 ) and hepatocytes ( 27 , 28 ). Of note, we recently reported that CD4 + Foxp3 + regulatory T cells (Tregs) have many active innate immunity pathways ( 29 , 30 ), and can sustain their immunosuppressive functions ( 31 ) in a proinflammatory atherogenic environment, although Tregs plasticity in atherosclerosis has been reported ( 32 , 33 ).…”