ArticleProceedings of the National Academy of Sciences of the United States of America2015
The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers, 1 of them a synthesis that pooled it.
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Who cites it
109 citing papers in PubMed, 1 synthesis or guideline pooled it, 159 citations in OpenAlex.
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- Amino Acids as Targets for Immunotherapy against Solid Tumors.Cell biochemistry and biophysics · 2026Review
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
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- Redox-metabolic circuits as a central regulator of T cell-based immunotherapy.Frontiers in immunology · 2026Review
- Neoepitopes at the crossroads of immunometabolism: metabolic remodeling of antigen presentation in type 1 diabetes.Frontiers in immunology · 2026Review
- GCN2 in Cancer: Molecular Mechanisms to Therapeutic Potential.Current cancer drug targets · 2026Review
- The Yin-Yang of Stress and Senescence: Integrated Stress Response and SASP Crosstalk in Stem Cell Fate, Regeneration, and Disease.Biocell : official journal of the Sociedades Latinoamericanas de Microscopia Electronica ... et. al · 2026Article
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- Metabolites in the extracellular tumor microenvironment and the shaping of macrophage function.Molecular cell · 2025Review
- Traditional medicine meets modern science: Halofuginone's role in combating autoimmune diseases.Journal of natural medicines · 2025Review
- Activation of the integrated stress response and loss of cFLIPCell death discovery · 2025Article
- Immunometabolism in systemic lupus erythematosus.Nature reviews. Rheumatology · 2025Review
- Nonessential amino acid is not nonessential in geriatric patients: implications for maxillofacial wound healing and bone repair.Maxillofacial plastic and reconstructive surgery · 2025Review
- Lymph node macrophages drive immune tolerance and resistance to cancer therapy by induction of the immune-regulatory cytokine IL-33.Cancer cell · 2025Article
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- EpicPred: predicting phenotypes driven by epitope-binding TCRs using attention-based multiple instance learning.Bioinformatics (Oxford, England) · 2025Article
- Harnessing amino acid pathways to influence myeloid cell function in tumor immunity.Molecular medicine (Cambridge, Mass.) · 2025Review
49 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Efficient apoptotic cell clearance and induction of immunologic tolerance is a critical mechanism preventing autoimmunity and associated pathology. Our laboratory has reported that apoptotic cells induce tolerance by a mechanism dependent on the tryptophan catabolizing enzyme indoleamine 2,3 dioxygenase 1 (IDO1) in splenic macrophages (MΦ). The metabolic-stress sensing protein kinase GCN2 is a primary downstream effector of IDO1; thus, we tested its role in apoptotic cell-driven immune suppression. In vitro, expression of IDO1 in MΦs significantly enhanced apoptotic cell-driven IL-10 and suppressed IL-12 production in a GCN2-dependent mechanism. Suppression of IL-12 protein production was due to attenuation of IL-12 mRNA association with polyribosomes inhibiting translation while IL-10 mRNA association with polyribosomes was not affected. In vivo, apoptotic cell challenge drove a rapid, GCN2-dependent stress response in splenic MΦs with increased IL-10 and TGF-β production, whereas myeloid-specific deletion of GCN2 abrogated regulatory cytokine production with provocation of inflammatory T-cell responses to apoptotic cell antigens and failure of long-tolerance induction. Consistent with a role in prevention of apoptotic cell driven autoreactivity, myeloid deletion of GCN2 in lupus-prone mice resulted in increased immune cell activation, humoral autoimmunity, renal pathology, and mortality. In contrast, activation of GCN2 with an agonist significantly reduced anti-DNA autoantibodies and protected mice from disease. Thus, this study implicates a key role for GCN2 signals in regulating the tolerogenic response to apoptotic cells and limiting autoimmunity.
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