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

Area of Science:

• Hepatology
• Immunology
• Metabolic Diseases

Background:

• Mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) are not fully understood, with chronic inflammation implicated.
• Mannose receptor type C 2 (MRC2) is investigated for its potential role in MASLD pathogenesis.

Purpose of the Study:

• To investigate the contribution of MRC2 to the development of MASLD.
• To elucidate the underlying molecular mechanisms involving macrophage-associated inflammation.

Main Methods:

• Utilized wild-type and MRC2-deficient mice fed a high-fat diet (HFD).
• Employed primary hepatocytes and bone marrow-derived macrophages stimulated with palmitic acid.
• Assessed the impact of MRC2 deficiency and CD147-NF-κB signaling on hepatic steatosis and TNF-α production.

Main Results:

• Elevated MRC2 levels correlated with MASLD severity in patients and mice.
• MRC2-deficient mice showed reduced HFD-induced weight gain and steatosis.
• Macrophage-derived MRC2 promoted steatosis via the MRC2-CD147 complex, impairing NF-κB signaling and TNF-α release.

Conclusions:

• Macrophage MRC2 drives hepatic steatosis in HFD-fed mice through the MRC2-CD147 complex.
• Targeting the macrophage MRC2-CD147 complex offers a novel therapeutic strategy for MASLD.