The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity.
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.
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Buvana
B
Ravishankar
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Haiyun
H
Liu
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Rahul
R
Shinde
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Kapil
K
Chaudhary
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Wei
W
Xiao
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
Jillian
J
Bradley
Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada M5G 2M9; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5T 1P5; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8;
Marianne
M
Koritzinsky
Section of Nephrology, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
Michael P
MP
Madaio
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912; Section of Nephrology, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912 tmcgaha@gru.edu.
Tracy L
TL
McGaha
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015551:Autoimmunity / Q000502:physiology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D007108:Immune Tolerance / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology; D007249:Inflammation; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D010880:Piperidines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000502:physiology*; D052999:Quinazolinones / Q000494:pharmacology; D015398:Signal Transduction
D000596:Amino Acids; D016207:Cytokines; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010880:Piperidines; D052999:Quinazolinones; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C010176:halofuginone
apoptosis; autoimmunity; immunometabolism; stress; tolerance