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CD44 is a key player in non-alcoholic steatohepatitis

  • Author Footnotes
    † These authors contributed equally as joint first authors.
    Stéphanie Patouraux
    Footnotes
    † These authors contributed equally as joint first authors.
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
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  • Author Footnotes
    † These authors contributed equally as joint first authors.
    Déborah Rousseau
    Footnotes
    † These authors contributed equally as joint first authors.
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
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  • Stéphanie Bonnafous
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
    Search for articles by this author
  • Cynthia Lebeaupin
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
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  • Carmelo Luci
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
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  • Clémence M. Canivet
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
    Search for articles by this author
  • Anne-Sophie Schneck
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
    Search for articles by this author
  • Adeline Bertola
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
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  • Marie-Christine Saint-Paul
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Biological Center, Pasteur Hôpital, Nice, France
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  • Antonio Iannelli
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
    Search for articles by this author
  • Jean Gugenheim
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
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  • Rodolphe Anty
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
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  • Albert Tran
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France

    CHU of Nice, Digestive Center, Nice, France
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  • Béatrice Bailly-Maitre
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
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  • Philippe Gual
    Correspondence
    Corresponding author. Address: INSERM U1065, Bâtiment Universitaire ARCHIMED, Equipe 8 “Complications hépatiques de l'obésité”, 151 route Saint Antoine de Ginestière, BP 2 3194, 06204 Nice Cedex 03, France. Tel.: +33 4 89 06 42 23; fax: +33 4 89 06 42 21.
    Affiliations
    INSERM, U1065, C3M, Team 8 “Hepatic Complications in Obesity”, Nice, France

    Université Côte d’Azur, Nice, France
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally as joint first authors.
Published:March 18, 2017DOI:https://doi.org/10.1016/j.jhep.2017.03.003

      Background & Aims

      Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression.

      Methods

      The role of CD44 was evaluated in CD44−/− mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n = 30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n = 64) were evaluated.

      Results

      Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44−/− mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p = 0.0008) and correlated with NAFLD activity score (NAS) (p = 0.001), ballooning (p = 0.003), alanine transaminase (p = 0.005) and hepatic CCL2 (p <0.001) and macrophage marker CD68 (p <0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44+ cells. Finally, the soluble form of CD44 increased with severe steatosis (p = 0.0005) and NASH (p = 0.007).

      Conclusion

      Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH.

      Lay summary

      Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy.

      Graphical abstract

      Keywords

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