Upregulation of MARCO in alveolar macrophages promotes CD5L-mediated angiogenesis in hepatopulmonary syndrome

Abstract Background Pulmonary angiogenesis drives hepatopulmonary syndrome (HPS), yet the role of alveolar macrophages (AMs) remains unclear. We aimed to elucidate the pro-angiogenic mechanisms of MARCO-upregulated AMs under bile acid and lipid dysregulation. Methods We established a common bile duct ligation (CBDL)-induced HPS rat model to identify disease-related genes via RNA-seq and intervened with the MARCO antagonist PolyG. In vitro, Sham AMs conditioned with Sham or CBDL serum were treated with oxidized low-density lipoprotein (Ox-LDL) neutralizing antibody, MARCO/CD5L siRNAs, taurocholic acid (TCA), or Ox-LDL, and co-cultured with pulmonary microvascular endothelial cells (PMVECs). Angiogenesis and barrier disruption were evaluated both in vivo and in vitro. Results Marco was identified as a key gene upregulated during disease progression in CBDL rat lung tissues via Kendall's rank correlation analysis of pathways of interest. In vitro, CBDL serum treatment of Sham AMs elevated MARCO and induced lipid droplet accumulation together with a pro-angiogenic phenotype. TCA alone was sufficient to upregulate MARCO, and co-treatment with Ox-LDL further triggered lipid droplet accumulation and pro-angiogenic behaviors, recapitulating CBDL serum effects. Ox-LDL phagocytosed by AMs activated the LXR/MafB pathway and promoted CD5L synthesis and secretion. Downregulation of MARCO or CD5L by siRNA attenuated the pro-angiogenic capacity of AMs, and in vivo administration of PolyG alleviated pulmonary angiogenesis and lung injury in HPS. Conclusion In HPS, TCA-induced MARCO upregulation in AMs drives excessive Ox-LDL phagocytosis, leading to CD5L secretion and subsequent pulmonary angiogenesis. Importantly, MARCO antagonism ameliorates HPS.