Annexin A1 treatment prevents the evolution to fibrosis of experimental nonalcoholic steatohepatitis (NASH)

Laila Lavanya Gadipudi, Naresh Naik Ramavath, Alessia Provera, Chris Reutelingsperger, Emanuele Albano*, Mauro Perretti, Salvatore Sutti

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Annexin A1 (AnxA1) is an important effector in the resolution of inflammation which is involved in modulating hepatic inflammation in nonalcoholic steatohepatitis (NASH). In this study we have investigated the possible effects of treatment with AnxA1 for counteracting the progression of experimental NASH. NASH was induced in C57BL/6 mice by feeding methionine-choline deficient (MCD) or Western diets and the animals were treated for 4-6 weeks with human recombinant AnxA1 (hrAnxA1; 1µg, daily IP) or saline once NASH was established. In both experimental models, treatment with hrAnxA1 improved parenchymal injury and lobular inflammation without interfering with the extension of steatosis. Furthermore, administration of hrAnxA1 significantly attenuated the hepatic expression of α1-procollagen and TGF-ß1 and reduced collagen deposition, as evaluated by collagen Sirius Red staining. Flow cytometry and immunohistochemistry showed that hrAnxA1 did not affect the liver recruitment of macrophages, but strongly interfered with the formation of crown-like macrophage aggregates and reduced their capacity of producing pro-fibrogenic mediators like osteopontin (OPN) and galectin-3 (Gal-3). This effect was related to an interference with the acquisition of a specific macrophage phenotype characterized by the expression of the Triggering Receptor Expressed on Myeloid cells 2 (TREM-2), CD9 and CD206, previously associated with NASH evolution to cirrhosis. Collectively, these results indicate that, beside ameliorating hepatic inflammation, AnxA1 is specifically effective in preventing NASH-associated fibrosis by interfering with macrophage pro-fibrogenic features. Such a novel function of AnxA1 gives the rational for the development of AnxA1 analogues for the therapeutic control of NASH evolution.

Original languageEnglish
Pages (from-to)643-656
JournalClinical Science
Issue number9
Publication statusE-pub ahead of print - 19 Apr 2022

Cite this