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

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.

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.

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.

Macrophage MRC2 promotes HFD-induced hepatic steatosis via the MRC2-CD147 complex, revealing a novel mechanism contributing to MASLD progression.

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.