Novel insights into GCN2 and mTOR signaling cross talk during efferocytosis 2828

Abstract Description The ability of cells to adapt to environmental changes is essential for their growth and survival. Eukaryotic cells, including macrophages (Mφ), utilize the GCN2 and mTOR pathways to regulate metabolism in response to microenvironmental cues. Efferocytosis (phagocytosis of apoptotic cells [AC]), plays a critical role in preventing autoimmunity and promoting immune tolerance. This process requires precise metabolic regulation, as Mφ must efficiently process AC-derived materials to control inflammation. While GCN2 and mTOR pathways are well-studied under amino acid deprivation, their roles in efferocytosis remain unclear. Here we show efferocytosis activates both mTORC1 and GCN2 in Mφ. Initial mTORC1 activation facilitates the recycling of AC-derived amino acids and cholesterol while down-regulating phagocytic receptors to mitigate efferocytosis-induced metabolic stress. Simultaneously, GCN2 activation promotes the production of anti-inflammatory cytokines and suppresses prolonged mTORC1 activity to prevent an inflammatory phenotype. Our findings reveal that GCN2-deficient Mφ displayed heightened mTORC1 activity, a pro-inflammatory phenotype, and impaired suppression of CD4 T cells after efferocytosis. These findings highlight the critical role of GCN2-mediated mTORC1 regulation in maintaining efferocytosis-driven immune tolerance in Mφ, with implications for cancer therapy and autoimmune disorders that require efficient efferocytosis. Funding Sources Supported by NIH/NCI 1R01CA255670; Medicine by design; the TFRI; and CIHR operating grants 406694, 436605, and 518004. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)