GPNMB regulates the differentiation and transformation of monocyte-derived macrophages during MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly concerning global health issue characterized by pronounced hepatic steatosis and liver fibrosis. Hepatic monocyte-derived macrophages (MDMs) are crucial in the pathogenesis of liver fibrosis under MASLD. Nevertheless, the precise functions of MDMs and the underlying mechanisms governing their differentiation remain inadequately elucidated. In this study, we revealed an orchestrator of this process: Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB), one of the characteristic genes of MDMs. Notably, myeloid-specific Gpnmb-knockout contributed to the retention of resident Kupffer cells (KCs) and rerouted monocyte differentiation towards a monocyte-derived macrophage subset that occupies the Kupffer cell niche (MoKC subset, resembling resident KCs), thereby impeding the formation of hepatic lipid-associated macrophages (LAMs). This transition has a profound impact, manifested in significantly reduced steatosis and modestly decreased liver fibrosis in myeloid-specific Gpnmb-knockout mice. In conclusion, our research clarifies the complex interactions between Gpnmb and MDMs and underscores the therapeutic potential of targeting Gpnmb within MDMs to manage MASLD.

Keywords: Differentiation; GPNMB; Kupffer cells; LAM; MASLD; MDM; Macrophage; MoKC.