Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice

Authors

  • Irene Locatelli,

    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
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  • Salvatore Sutti,

    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
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  • Aastha Jindal,

    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
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  • Marco Vacchiano,

    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
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  • Cristina Bozzola,

    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
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  • Chris Reutelingsperger,

    1. Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
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  • Dennis Kusters,

    1. Cardiovascular Research Institute Maastricht, Department of Biochemistry, Maastricht University, Maastricht, The Netherlands
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  • Stefania Bena,

    1. William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; and Departments of, Turin, Italy
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  • Maurizio Parola,

    1. Clinical and Biological Sciences, University of Turin, Turin, Italy
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  • Claudia Paternostro,

    1. Clinical and Biological Sciences, University of Turin, Turin, Italy
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  • Elisabetta Bugianesi,

    1. Medical Sciences, University of Turin, Turin, Italy
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  • Simon McArthur,

    1. William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; and Departments of, Turin, Italy
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  • Emanuele Albano,

    Corresponding author
    1. Department of Health Sciences and Interdisciplinary Research Center for Autoimmune Diseases, University “Amedeo Avogadro” of East Piedmont, Novara, Italy
    • Address reprint requests to: Prof. Emanuele Albano, M.D., Ph.D., Department of Health Science, University “Amedeo Avogadro” of East Piedmont, Via Solaroli 17, 28100 Novara, Italy. E-mail: emanuele.albano@med.unipmn.it; fax: +39 0321 620421.

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    • These authors share senior authorship.

  • Mauro Perretti

    1. William Harvey Research Institute, Queen Mary University of London, London, United Kingdom; and Departments of, Turin, Italy
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    • These authors share senior authorship.


  • Potential conflict of interest: Nothing to report.

  • This work has been supported by grants from the Fondazione Cariplo, Milan, Italy (grant no.: 2011-0470), The Wellcome Trust (Programme 086867/Z/08/Z) and, in part, The William Harvey Research Foundation (London, UK). I.L. Ph.D. training at the Scuola di Alta Formazione of the University of East Piendmont was supported by the Compagnia di San Paolo (Turin, Italy) and partially by the Fondazione Cariplo (NutriAl Network 2010).

Abstract

Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. However, its role in chronic settings is less investigated. Because changes in AnxA1 expression within adipose tissue characterize obesity in mice and humans, we queried a possible role for AnxA1 in the pathogenesis of nonalcoholic steatohepatitis (NASH), a disease commonly associated with obesity. NASH was induced in wild-type (WT) and AnxA1 knockout (AnxA1 KO) C57BL/6 mice by feeding a methionine-choline deficient (MCD) diet up to 8 weeks. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury. This mediator was also detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. In both humans and rodents, AnxA1 production was selectively localized in liver macrophages. NASH in AnxA1 KO mice was characterized by enhanced lobular inflammation resulting from increased macrophage recruitment and exacerbation of the M1 phenotype. Consistently, in vitro addition of recombinant AnxA1 to macrophages isolated from NASH livers down-modulated M1 polarization through stimulation of interleukin-10 production. Furthermore, the degree of hepatic fibrosis was enhanced in MCD-fed AnxA1 KO mice, an effect associated with augmented liver production of the profibrotic lectin, galectin-3. Accordingly, AnxA1 addition to isolated hepatic macrophages reduced galectin-3 expression. Conclusions: Macrophage-derived AnxA1 plays a functional role in modulating hepatic inflammation and fibrogenesis during NASH progression, suggesting the possible use of AnxA1 analogs for therapeutic control of this disease. (Hepatology 2014;60:531–544)

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