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Redox-sensitive activation of CCL7 by BRG1 in hepatocytes during liver injury.

ABSTRACT: Liver injuries induced by various stimuli share in common an acute inflammatory response, in which circulating macrophages home to the liver parenchyma to participate in the regulation of repair, regeneration, and fibrosis. In the present study we investigated the role of hepatocyte-derived C-C motif ligand 7 (CCL7) in macrophage migration during liver injury focusing on its transcriptional regulation. We report that CCL7 expression was up-regulated in the liver by lipopolysaccharide (LPS) injection (acute liver injury) or methionine-and-choline-deficient (MCD) diet feeding (chronic liver injury) paralleling increased macrophage infiltration. CCL7 expression was also inducible in hepatocytes, but not in hepatic stellate cells or in Kupffer cells, by LPS treatment or exposure to palmitate in vitro. Hepatocyte-specific deletion of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, resulted in a concomitant loss of CCL7 induction and macrophage infiltration in the murine livers. Of interest, BRG1-induced CCL7 transcription and macrophage migration was completely blocked by the antioxidant N-acetylcystine. Further analyses revealed that BRG1 interacted with activator protein 1 (AP-1) to regulate CCL7 transcription in hepatocytes in a redox-sensitive manner mediated in part by casein kinase 2 (CK2)-catalyzed phosphorylation of BRG1. Importantly, a positive correlation between BRG1/CCL7 expression and macrophage infiltration was identified in human liver biopsy specimens. In conclusion, our data unveil a novel role for BRG1 as a redox-sensitive activator of CCL7 transcription.

SUBMITTER: Kong M

PROVIDER: S-EPMC8406035 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IFN?I signaling exacerbate liver pathology and contribute to sepsis following fatal Ehrlichia infection by promoting Ehrlichia replication and mediating detrimental inflammasome activation. Inflammasomes are an important innate immune host defense against intracellular microbial infection. Activation of inflammasomes by microbial or host ligands results in cleavage of caspase?1 (canonical pathway) or caspase?11 (noncanonical pathway), release of interleukin (IL)?1?, IL?18, high mobility group box 1 (HMGB1), and inflammatory cell death known as pyroptosis. Ehrlichia are obligate, intracellular, gram?negative bacteria that lack lipopolysaccharide but cause potentially life?threatening monocytic ehrlichiosis in humans and mice that is characterized by liver injury followed by sepsis and multiorgan failure. Employing murine models of mild and fatal ehrlichiosis caused by infection with mildly and highly virulent Ehrlichia muris (EM) and Ixodes ovatus Ehrlichia (IOE), respectively, we have previously shown that IOE infection triggers type I interferon (IFN?I) response and deleterious caspase?11 activation in liver tissues, which promotes liver injury and sepsis. In this study, we examined the contribution of IFN?I signaling in hepatocytes (HCs) to Ehrlichia?induced liver injury. Compared to EM infection, we found that IOE enter and replicate in vitro cultured primary murine HCs and induce secretion of IFN? and several chemokines, including regulated upon activation, normal T?cell expressed, and secreted (RANTES), monocyte chemoattractant protein 1 (MCP1), monokine induced by gamma (MIG)/chemokine (C?X?C motif) ligand 9 (CXCL9), macrophage inflammatory protein 1 alpha (MIP1?), keratinocyte?derived chemokine (KC), and granulocyte?macrophage colony?stimulating factor (GM?CSF). Notably, in vitro stimulation of uninfected and Ehrlichia?infected HCs with recombinant IFN? triggered activation of caspase?1/11, cytosolic translocation of HMGB1, and enhanced autophagy and intracellular bacterial replication. Secretion of HMGB1 by IOE?infected HCs was dependent on caspase?11. Primary HCs from IOE? but not EM?infected mice also expressed active caspase?1/11. Conclusion: HC?specific IFN?I signaling may exacerbate liver pathology during infection with obligate intracellular Ehrlichia by promoting bacterial replication and detrimental caspase?11?mediated inflammasome activation.

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Redox-sensitive activation of CCL7 by BRG1 in hepatocytes during liver injury.

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