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

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 neurite outgrowth inhibitor protein B (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 Results: Septic conditions upregulated Nogo-B expression and impaired efferocytosis in monocytes and MDMs, but not in peritoneal macrophages or Kupffer cells (n = 3-7, Conclusions: Nogo-B impairs MDM efferocytosis by suppressing OXPHOS and activating HIF-1α/ADAM17 signaling, thereby exacerbating septic liver and lung injury. Targeting Nogo-B offers a novel strategy to restore efferocytosis and alleviate sepsis. Impact and implications: Efferocytosis is compromised during sepsis, contributing to enhanced inflammation and organ damage. Our study identified Nogo-B as a critical mediator linking disrupted mitochondrial calcium uptake to impaired MDM efferocytosis. Targeting Nogo-B may represent a novel therapeutic strategy to restore efferocytosis and attenuate sepsis-related tissue injury. Further translational studies are needed to validate these findings in human disease.