Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis

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.

Vicious Cycle‐Breaking Lipid Nanoparticles Remodeling Multicellular Crosstalk to Reverse Liver Fibrosis

“…The fluorescence intensity of CS-NPs/VDGtreated group was even lower than that of control group, which may be explained by that in vitro cultured HSCs would be partially activated when cultured in 10% FBS DMEM. [40] In a further experiment, HSCs-LSECs coculture system was applied to explore the possibility of inhibiting HSCs activation to prevent the loss of fenestrae and phenotype transformation of LSECs (Figure 3G). Immuno-staining of CD31 (a classic marker of capillarized LSECs) showed that HSCs pretreated with TGF-𝛽 and CS-NPs/VDG could reverse LSECs capillarization process.…”