Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Meghan Mooring, Grace A. Yeung, Panu K. Luukkonen, Silvia Liu, Muhammad Waqas Akbar, Gary J. Zhang, Oluwashanu Balogun, Xuemei Yu, Rigen Mo, Kari Nejak‐Bowen, Masha V. Poyurovsky, Carmen J. Booth, Liza Konnikova, Gerald I. Shulman, Dean Yimlamai
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.