Work

Macrophage MRC2 deficiency mitigates HFD-induced MASLD by downregulating CD147-regulated TNF-α production

Year: 2025

Type: article

Abstract: Background & Aims The mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain incompletely understood, and macrophage-associated chronic inflammation has been suggested to play a role. We investigated the potential contribution of mannose receptor type C 2 (MRC2), a transmembrane glycoprotein, to MASLD development. Methods Wild-type (WT) and Mrc 2 -deficient mice were fed a high-fat diet (HFD) for 8 weeks. Mouse primary hepatocytes (MPHs) and bone marrow–derived macrophages (BMDMs) were stimulated with or without palmitic acid (PA) to assess the role of MRC2 in MASLD development. Results MRC2 levels were significantly elevated in patients with MASLD (n = 216, p < 0.0001) and in the livers of HFD-fed WT mice (n = 6–8, p < 0.01), correlating with disease severity. Mrc 2 -null mice exhibited reduced HFD-induced weight gain and steatosis compared with WT mice (n = 6–8). MRC2 was predominantly expressed in hepatic macrophages, and conditioned medium from WT BMDMs enhanced PA-induced steatosis in MPHs (n = 6, p < 0.0001). This effect was absent when conditioned medium from Mrc 2 -deficient BMDMs was used or when TNF-α–neutralizing antibodies or TNF receptor antagonists were added. Macrophage-specific Mrc2 deficiency also reduced MASLD severity in HFD-fed mice (n = 6). Mechanistically, disruption of the MRC2–CD147 complex impaired CD147-mediated NF-κB signaling and reduced TNF-α release from BMDMs, thereby decreasing steatosis in co-cultured MPHs. Conclusions Macrophage MRC2 promotes HFD-induced hepatic steatosis via the MRC2–CD147 complex, revealing a novel mechanism contributing to MASLD progression. Impact and implications This study identifies the critical role of MRC2 in the development of high-fat diet-induced metabolic dysfunction-associated steatotic liver disease, providing a mechanistic understanding of its involvement in macrophage-mediated inflammation. M rc 2 deficiency alleviates hepatic inflammation and lipid accumulation by downregulating CD147-regulated TNF-α production in macrophages. The findings are particularly significant for researchers and clinicians focused on liver diseases, as they reveal a novel target – the macrophage MRC2-CD147 complex – for potential therapeutic intervention.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2025.101601