CD74 accumulation in macrophages suppresses efferocytosis and exacerbates atherosclerosis by interfering with myosin II function.

Abstract

Defective macrophage efferocytosis is a critical driver of the progression of inflammatory diseases such as atherosclerosis (AS), yet whether Cluster of Differentiation 74 (CD74) participates in this process remains unclear. In this study, using RAW264.7 macrophages as a model, we found that pharmacological inhibition of Cathepsin S with RO5459072 led to aberrant lysosomal accumulation of CD74 and markedly impaired efferocytosis. Mechanistically, co-immunoprecipitation (Co-IP) confirmed that CD74 forms a complex with myosin II. Under conditions of CD74 overexpression, siRNA-mediated silencing of myosin II further exacerbated the suppression of efferocytosis, accompanied by reduced myosin light chain 2 (MLC2) phosphorylation and downregulated expression of the bridging molecules MFGE8 and GAS6. In vivo, CD74 overexpression in APOE-/- mice aggravated aortic plaque burden, increased lipid deposition and collagen content, and reduced macrophage infiltration within plaques. Collectively, these findings suggest that dysregulation of the Cathepsin S-CD74-myosin II axis may impact AS progression by interfering with macrophage efferocytosis, offering a potential novel entry point for therapeutic intervention in AS.