Nogo-B impairs efferocytosis in monocyte-derived macrophages and exacerbates septic liver injury

作者：Weizhe Zhong, Jian Xu, Fei Li, Zhu Guan, Haoran Hu, Dongming Wu, Yuechen Wang, Ye Zhang, Yan Bai, Yue Yu, Yun Gao, Ping Wang, Xiongxiong Pan, Zhuqing Rao, Haoming Zhou, Xuehao Wang · 发表于：JHEP Reports · 年份：2025 · DOI：10.1016/j.jhepr.2025.101556 · 被引用次数：4 · 研究领域：Phagocytosis and Immune Regulation、Immune cells in cancer、Immune responses and vaccinations

Background & Aims Efferocytosis is essential for maintaining tissue homeostasis and resolving inflammation, but this process is compromised during sepsis. This study aimed to elucidate the role of Nogo-B in regulating macrophage efferocytosis under septic conditions and to evaluate its potential as a therapeutic target. Methods We evaluated Nogo-B expression and efferocytosis in monocytes and monocyte-derived macrophages (MDMs) under septic conditions. Myeloid-specific Nogo deletion was used to assess its impact on MDM efferocytosis and septic organ injury. Mechanistic studies examined HIF-1α/ADAM17 signaling, mitochondrial calcium dynamics, metabolic activity, and endoplasmic reticulum (ER) stress. INCB081776, a dual MerTK/AXL inhibitor, was administered in vivo to suppress efferocytosis prior to mouse modeling. Statistical comparisons were performed using t-tests or ANOVA. Results Septic conditions upregulated Nogo-B expression and impaired efferocytosis in monocytes and MDMs, but not in peritoneal macrophages (PMs) or Kupffer cells (KCs) (n=3-7, p<0.05). Myeloid Nogo deficiency significantly enhanced MDM efferocytosis and alleviated inflammatory liver and lung injury (n=7, p<0.05). Mechanistically, Nogo-B disrupted ER-mitochondria calcium transfer, reduced mitochondrial calcium levels, and suppressed isocitrate dehydrogenase (IDH) and succinate dehydrogenase (SDH) activity. This led to impaired TCA cycle function and OXPHOS, resulting in succinate accumulation and an eleva...