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TNF-Like Ligand 1 Aberrance Aggravates Nonalcoholic Steatohepatitis via M1 Macrophage Polarization.

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is a progressive, chronic liver disease worldwide which imposes a large economic burden on society. M1/M2 macrophage balance destruction and recruitment of mononuclear immune cells to the liver play critical roles in NASH. Several studies have shown that the expression of TNF-like ligand 1 aberrance (TL1A) increased in macrophages associated with many inflammatory diseases, for example, inflammatory bowel disease, primary biliary cholangitis, and liver fibrosis. One recent research showed that weight, abdominal adipose, and liver leptin, one of the critical fat cytokines, were reduced in TL1A knockout mice. However, the functional and molecular regulatory mechanisms of TL1A on macrophage polarization and recruitment in NASH have yet to be clarified. The authors found that high fructose high fat diet and methionine-choline deficiency diet induced the expression of TL1A in macrophages of liver tissue from murine NASH models. Myeloid-specific TL1A overexpressed mice showed exacerbated steatohepatitis with increased hepatic lipid accumulation, inflammation, liver injury, and apoptosis. M1 macrophages' infiltration and the production of proinflammatory and chemotactic cytokines increased in liver of NASH mouse models with myeloid-specific TL1A overexpressed. Furthermore, this paper revealed that bone marrow-derived macrophages and Kupffer cells with overexpression of TL1A exacerbated the lipid accumulation and expression of proinflammatory factors in the murine primary hepatocytes after free fatty acid treatment in vitro. In conclusion, TL1A-mediated M1-type macrophage polarization and recruitment into the liver promoted steatohepatitis in murine NASH.

SUBMITTER: Luo Y

PROVIDER: S-EPMC8741351 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study aimed to investigate the beneficial effects of myricetin in a diet-induced nonalcoholic steatohepatitis (NASH) model and the underlying mechanism. C57BL/6J mice were fed a standard chow or the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks with the treatment of myricetin (100 mg/kg) or vehicle by daily gavage. Hepatic inflammation, steatosis, fibrosis, and hepatic stellate cells (HSC) activation were assessed. We also analyzed M1 and M2 macrophages and its related markers in livers from NASH mice and in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS) or interleukin 4 (IL-4) in vitro. Furthermore, we determined the effect of myricetin on the triggering receptor expressed on myeloid cells-1 (TREM-1), toll like receptor (TLR) 2 and 4, and myeloid differentiation factor 88 (MyD88) signaling both in livers from mice and in RAW264.7 cells stimulated by LPS. Our results revealed that myricetin remarkably ameliorated hepatic steatosis, inflammation, and inhibited hepatic macrophage infiltration in CDAHFD-fed mice. Myricetin-treated to CDAHFD-fed mice also inhibited liver fibrosis and HSC activation when compared with vehicle-treated to those mice. Moreover, myricetin inhibited M1 macrophage polarization and its relative markers in livers of NASH mice while induced M2 polarization. Similarly, in vitro study, myricetin inhibited the LPS-induced mRNA expression of M1 macrophages marker genes and induced IL-4-induced M2 macrophage marker genes in RAW264.7 macrophages. Mechanically, myricetin inhibited the expression of TREM-1 and TLR2/4-MyD88 signaling molecules in livers from NASH mice and in RAW264.7 macrophages stimulated by LPS in vitro. Additionally, myricetin inhibited the activation of nuclear factor (NF)-?B signaling and the phosphorylation of the signal transducer and activation of transcription 3 (STAT3) in LPS-stimulated RAW264.7 macrophages. Taken together, our data indicated that myricetin modulated the polarization of macrophages via inhibiting the TREM-1-TLR2/4-MyD88 signaling molecules in macrophages and therefore mitigated NASH and hepatic fibrosis in the CDAHFD-diet-induced NASH model in mice.

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TNF-Like Ligand 1 Aberrance Aggravates Nonalcoholic Steatohepatitis via M1 Macrophage Polarization.

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