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

Buvana Ravishankara, Haiyun Liua, Rahul Shindea, Kapil Chaudharya, Wei Xiaoa, Jillian Bradleya, Marianne Koritzinsky, Michael P. Madaio, Tracy L. McGaha

Research output: Contribution to journalArticle

44 Scopus citations

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 (MPdbl). 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 MPdbls significantly enhanced apoptotic celldriven 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 MPdbls 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.

Original languageEnglish (US)
Pages (from-to)10774-10779
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number34
DOIs
StatePublished - Aug 25 2015

    Fingerprint

Keywords

  • Apoptosis
  • Autoimmunity
  • Immunometabolism
  • Stress
  • Tolerance

ASJC Scopus subject areas

  • General

Cite this