Regulation of Macrophage Efferocytosis by the CXCL10–CXCR3 Axis and CD36 in Acute Lung Injury

Background: Macrophage efferocytosis is the primary mechanism for clearing apoptotic cells (ACs) in vivo and is critical for maintaining tissue homeostasis. In acute lung injury (ALI), the C-X-C motif chemokine ligand 10 (CXCL10)–C-X-C motif chemokine receptor 3 (CXCR3) axis is upregulated and contributes significantly to pulmonary inflammation by regulating macrophage migration, invasion, polarization, and autophagy. However, whether this axis directly modulates macrophage efferocytosis remains unknown. Methods: ALI models, both in vivo and in vitro, models were used to assess the impact of CXCL10–CXCR3 axis on macrophage efferocytosis. Using the CXCR3 antagonist AMG487, we assessed efferocytic capacity and examined the cluster of differentiation 36 (CD36)-ubiquitin-like 4A (UBL4A) interaction under inflammatory conditions, revealing that UBL4A-mediated CD36 degradation regulates efferocytosis. Results: Efferocytosis was impaired in lung tissue and macrophages in ALI. Blocking the CXCL10–CXCR3 axis significantly enhanced efferocytosis in vivo. Mechanistically, inflammatory conditions promoted CD36 degradation by upregulating UBL4A. Treatment with AMG487 downregulated UBL4A expression, thereby preventing CD36 degradation and preserving efferocytosis in vivo, while attenuating UBL4A-mediated CD36 ubiquitination and degradation in vitro. Conclusions: The CXCL10–CXCR3 axis negatively regulates macrophage efferocytosis during ALI through UBL4A-mediated CD36 degradation. Targeting this axis with AMG487 preserves efferocytosis by restoring CD36 levels, suggesting that this approach represents a potential therapeutic strategy for ALI and establishing a theoretical foundation for future targeted interventions.