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Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

ABSTRACT: Matrix remodeling associated 7 (MXRA7) was first noted to co-express with a group of matrix remodeling related genes, and its biological functions had remained unclear. In this study, we investigated the presumed function of MXRA7 in a carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Wild-type, MXRA7-/- mice, and mice that were pulsed with hydrodynamic injection of vehicle or MXRA7-harboring plasmids were challenged with a single dose of CCl4 for injury induction. The sera, spleens, and livers were harvested from mice for assay of cytokines/chemokines expression, cellular responses, or histological features. We found that MXRA7 deficiency alleviated, and MXRA7 overexpression aggravated liver damage in CCl4-challenged mice. FACS analysis showed that MXRA7 deficiency reduced the recruitment of neutrophils through downregulation the expression of CXCL1 and CXCL2 in liver, decreased the number of CD8+ T cells in liver and spleen, suppressed the release of IFN? and TNF? from T cells, and decreased IFN? in serum and liver. Western blot assay demonstrated that MXRA7 deficiency suppressed the activation of MAPK pathway and AKT/NF-?B pathway, respectively. Lastly, MXRA7 deficiency or overexpression regulated the expression of two matrix remodeling-related genes (fibronectin and TIMP1) in the liver. We concluded that MXRA7 was an active player in CCl4-induced liver injury, hypothetically by mediating the inflammation or immune compartments and matrix remodeling processes. Further exploration of MXRA7 as a possible new therapeutic target for management of inflammation-mediated liver injury was discussed.

SUBMITTER: Lin D

PROVIDER: S-EPMC5915751 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

Lin Dandan D Sun Zhenjiang Z Jin Ziqi Z Lei Lei L Liu Yonghao Y Hu Bo B Wang Benfang B Shen Ying Y Wang Yiqiang Y

Frontiers in immunology 20180418

Matrix remodeling associated 7 (MXRA7) was first noted to co-express with a group of matrix remodeling related genes, and its biological functions had remained unclear. In this study, we investigated the presumed function of MXRA7 in a carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Wild-type, MXRA7-/- mice, and mice that were pulsed with hydrodynamic injection of vehicle or MXRA7-harboring plasmids were challenged with a single dose of CCl4 ...[more]

PMID: 29720975

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Project description:Polarization of hepatic macrophages plays a crucial role in the injury and repair processes of acute and chronic liver diseases. However, the underlying molecular mechanisms remain elusive. Caveolin-1 (Cav1) is the structural protein of caveolae, the invaginations of the plasma membrane. It has distinct functions in regulating hepatitis, cirrhosis, and hepatocarcinogenesis. Given the increasing number of cases of liver cancer, nonalcoholic steatohepatitis, and non-alcoholic fatty liver disease worldwide, investigations on the role of Cav1 in liver diseases are warranted. In this study, we aimed to investigate the role of Cav1 in the pathogenesis of acute liver injury. Wild-type (WT) and Cav1 knockout (KO) mice (Cav1tm1Mls) were injected with carbon tetrachloride (CCl4). Cav1 KO mice showed significantly reduced degeneration, necrosis, and apoptosis of hepatocytes and decreased level of alanine transaminase (ALT) compared to WT mice. Moreover, Cav1 was required for the recruitment of hepatic macrophages. The analysis of the mRNA levels of CD86, tumor necrosis factor (TNF), and interleukin (IL)-6, as well as the protein expression of inducible nitric oxide synthase (iNOS), indicated that Cav1 deficiency inhibited the polarization of hepatic macrophages towards the M1 phenotype in the injured liver. Consistent with in vivo results, the expressions of CD86, TNF, IL-6, and iNOS were significantly downregulated in Cav1 KO macrophages. Also, fluorescence-activated cell sorting (FACS) analysis showed that the proportion of M1 macrophages was significantly decreased in the liver tissues obtained from Cav1 KO mice following CCl4 treatment. In summary, our results showed that Cav1 deficiency protected mice against CCl4-induced acute liver injury by regulating polarization of hepatic macrophages. We provided direct genetic evidence that Cav1 expressed in hepatic macrophages contributed to the pathogenesis of acute liver injury by regulating the polarization of hepatic macrophages towards the M1 phenotype. These findings suggest that Cav1 expressed in macrophages may represent a potential therapeutic target for acute liver injury.

Project description:Transforming growth factor-beta1 (TGF-β1) is a major factor in pathogenesis of chronic hepatic injury. Carbon tetrachloride (CCl4) is a liver toxicant, and CCl4-induced liver injury in mouse is a classical animal model of chemical liver injury. However, it is still unclear whether TGF-β1 is involved in the process of CCl4-induced acute chemical liver injury. The present study aimed to evaluate the role of TGF-β1 and its signaling molecule Smad3 in the acute liver injury induce by CCl4. The results showed that CCl4 induced acute liver injury in mice effectively confirmed by H&E staining of liver tissues, and levels of not only liver injury markers serum ALT and AST, but also serum TGF-β1 were elevated significantly in CCl4-treated mice, compared with the control mice treated with olive oil. Our data further revealed that TGF-β1 levels in hepatic tissue homogenate increased significantly, and type II receptor of TGF-β (TβRII) and signaling molecules Smad2, 3, mRNA expressions and Smad3 and phospho-Smad3 protein levels also increased obviously in livers of CCl4-treated mice. To clarify the effect of the elevated TGF-β1/Smad3 signaling on CCl4-induced acute liver injury, Smad3 in mouse liver was overexpressed in vivo by tail vein injection of Smad3-expressing plasmids. Upon CCl4 treatment, Smad3-overexpressing mice showed more severe liver injury identified by H&E staining of liver tissues and higher serum ALT and AST levels. Simultaneously, we found that Smad3-overexpressing mice treated with CCl4 showed more macrophages and neutrophils infiltration in liver and inflammatory cytokines IL-1β and IL-6 levels increment in serum when compared with those in control mice treated with CCl4. Moreover, the results showed that the apoptosis of hepatocytes increased significantly, and apoptosis-associated proteins Bax, cytochrome C and the cleaved caspase 3 expressions were up-regulated in CCl4-treated Smad3-overexpressing mice as well. These results suggested that TGF-β1/Smad3 signaling was activated during CCl4-induced acute liver injury in mice, and Smad3 overexpression aggravated acute liver injury by promoting inflammatory cells infiltration, inflammatory cytokines release and hepatocytes apoptosis. In conclusion, the activation of TGF-β signaling contributes to the CCl4-induced acute liver injury. Thus, TGF-β1/Smad3 may serve as a potential target for acute liver injury therapy.

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Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

Publications

Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

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