Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10774-9. doi: 10.1073/pnas.1504276112. Epub 2015 Aug 10.

The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity.

Author information

1
Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA 30912;
2
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;
3
Section of Nephrology, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912.
4
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.

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.

KEYWORDS:

apoptosis; autoimmunity; immunometabolism; stress; tolerance

PMID:
26261340
PMCID:
PMC4553766
DOI:
10.1073/pnas.1504276112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center