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Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis.

ABSTRACT: Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages, which decreased their secretion of proinflammatory cytokines in a dose-dependent manner. The inactivation of macrophages attenuated lipopolysaccharide-induced injurious inflammation concurrent with a reduction in F4/80+ cells, proinflammatory cytokine levels, and neutrophil infiltration. Moreover, compound 38 inhibited the Wnt/β-catenin and transforming growth factor-beta/SMAD signaling pathways to abolish the activation of HSCs. In vivo, compound 38 significantly decreased the collagen deposition and fibrotic area of a CCl₄-induced liver fibrosis model, and restored the deficiency of activated HSCs and the upregulation of liver inflammation. These results highlight the potential role of compound 38 in treating liver fibrosis considering its simultaneous inhibitory effects on liver inflammation and related fibrosis.

SUBMITTER: Fu R

PROVIDER: S-EPMC9278415 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis.

Fu Rong R Zu Shi-Jia SJ Liu Yan-Jun YJ Li Jia-Cheng JC Dang Wen-Zhen WZ Liao Li-Ping LP Liu Li-Ping LP Chen Pan-Yu PY Huang He-Ming HM Wu Kang-Hui KH Zhou Bing B Pan Qin Q Luo Cheng C Zhang Yuan-Yuan YY Li Guang-Ming GM

Bioengineered 20220401 4

Liver fibrosis occurs following inflammation triggered by the integrated actions of activated liver-resident macrophages (Kupffer cells) and hepatic stellate cells (HSCs), and the multiplicity of these mechanisms complicates drug therapy. Here, we demonstrate that the selective bromodomain and extra-terminal (BET) bromodomain inhibitor compound38 can block both the Janus kinase-signal transducer and activator of transcription and mitogen-activated protein kinase signaling pathways in macrophages ...[more]

PMID: 35499161

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Project description:BackgroundThe role of GLIS2 in fibrotic diseases is controversial. GLIS2 deficiency has been reported to contribute to renal fibrosis in mice and has also been reported to prevent high lipid-induced mice hepatic fibrosis.MethodsHepatic fibrosis in mice was induced by CCl4. Hematoxylin and eosin, Masson, Sirius red, and enzyme-linked immunosorbent assay were used to detect and evaluate the stage of hepatic fibrosis in humans or mice. A study model of tetracycline-responsive GLIS2 knockout hepatic stellate cells (HSCs) was constructed and named GLIS2-SG-Dox. By adding transforming growth factor β1 to stimulate the transdifferentiation of HSCs, the activation status of HSCs was comprehensively evaluated from the aspects of cell proliferation, migration, and the amount of lipid droplets. In mechanistic studies, dual-luciferase, coimmunoprecipitation, yeast two-hybrid system, chromatin immunoprecipitation, and DNA pulldown were performed to investigate or to prove the molecular mechanism that GLIS2 was involved in regulating liver fibrosis. Throughout the study, real-time fluorescence polymerase chain reaction (quantitative reverse-transcription polymerase chain reaction) was used to detect the relative abundance of messenger RNA expression of each target gene, Western blot was used to detect the relative abundance of protein, and immunohistochemistry or immunofluorescence was used to observe the subcellular localization of the target protein.ResultsThe expression of GLIS2 was significantly decreased in human liver fibrosis tissues and CCL4-induced mouse liver fibrosis tissues, especially in HSCs. In the GLIS2-SG-Dox cells, the peroxisome proliferator-activated receptor γ (PPAR-γ) pathway was inactive and cells underwent myofibroblastic transdifferentiation transformation. Overexpression of GLIS2 can increase the acetylation level of PPAR-γ and alleviate CCL4-induced liver fibrosis in mice. Mechanically, relatively abundant GLIS2 and histone deacetylase 3 (HDAC3) form chelates to avoid the deacetylation of PPAR-γ, so as to maintain the activation level of PPAR-γ signaling pathway in HSCs cells. In this process, HDAC3 acts as a medium for GLIS2 to influence PPAR-γ signaling. Nonetheless, when GLIS2 is absent, HDAC3 deacetylates PPAR-γ, activates HSCs, and leads to liver fibrosis.ConclusionsGLIS2 deficiency promotes myofibroblastic transdifferentiation and activation of HSCs. Mechanically, GLIS2 regulates the acetylation of PPAR-γ by competitively binding to HDAC3 in HSCs.

Dataset Information

Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis.

Publications

Selective bromodomain and extra-terminal bromodomain inhibitor inactivates macrophages and hepatic stellate cells to inhibit liver inflammation and fibrosis.

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