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 in vivo to suppress efferocytosis before 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 or Kupffer cells (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 and succinate dehydrogenase activities. This led to impaired tricarboxylic acid (TCA) cycle function and oxidative phosphorylation (OXPHOS), resulting in succinate accumulation and an elevated succinate/α-ketoglutarate ratio. The metabolic shift activated HIF-1α/ADAM17 signaling, promoting MerTK/AXL cleavage and further impairing efferocytosis. Nogo deficiency also promoted MDM M2 polarization without affecting ER stress under lipopolysaccharide stimulation. Pharmacological inhibition of MerTK/AXL reversed the beneficial effects of myeloid Nogo deficiency on efferocytosis and septic liver and lung injury (n = 5, p <0.05). 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.