Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis

  • Sci Transl Med. 2023 Sep 27;15(715):eade3157. doi: 10.1126/scitranslmed.ade3157.
Meghan Mooring  1  2 ,  Grace A Yeung  2 ,  Panu Luukkonen  3 ,  Silvia Liu  4  5 ,  Muhammad Waqas Akbar  2 ,  Gary J Zhang  2 ,  Oluwashanu Balogun  1  4 ,  Xuemei Yu  6 ,  Rigen Mo  6 ,  Kari Nejak-Bowen  1  4  5 ,  Masha V Poyurovsky  6 ,  Carmen J Booth  7 ,  Liza Konnikova  8 ,  Gerald I Shulman  3  9 ,  Dean Yimlamai  1  2  5  10
Affiliations
  • 1. Department of Cellular and Molecular Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 2. Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Yale School of Medicine, New Haven, CT 06514, USA.
  • 3. Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06514, USA.
  • 4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 5. Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 6. Kadmon Corporation LLC, 450 East 29th Street, New York, NY 10016, USA.
  • 7. Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06514, USA.
  • 8. Section of Neonatology, Department of Pediatrics, Yale School of Medicine, New Haven, CT 06514, USA.
  • 9. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06514, USA.
  • 10. Yale Liver Center, Yale School of Medicine, New Haven, CT 06514, USA.
PMID: 37756381 DOI: 10.1126/scitranslmed.ade3157
Abstract

Obesity is increasing worldwide and leads to a multitude of metabolic diseases, including Cardiovascular Disease, type 2 diabetes, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis (NASH). Cysteine-rich angiogenic inducer 61 (CYR61) is associated with the progression of NASH, but it has been described to have anti- and proinflammatory properties. We sought to examine the role of liver CYR61 in NASH progression. CYR61 liver-specific knockout mice on a NASH diet showed improved glucose tolerance, decreased liver inflammation, and reduced fibrosis. CYR61 polarized infiltrating monocytes promoting a proinflammatory/profibrotic phenotype through an IRAK4/Syk/NF-κB signaling cascade. In vitro, CYR61 activated a profibrotic program, including PDGFa/PDGFb expression in macrophages, in an IRAK4/Syk/NF-κB-dependent manner. Furthermore, targeted-antibody blockade reduced CYR61-driven signaling in macrophages in vitro and in vivo, reducing fibrotic development. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis in NASH.

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