Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Buvana Ravishankar, Haiyun Liu, Rahul Shinde, Phillip Chandler, Babak Baban, Masato Tanaka, David H. Munn, Andrew L. Mellor, Mikael C I Karlsson, Tracy L. McGaha

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.

Original languageEnglish (US)
Pages (from-to)3909-3914
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number10
DOIs
StatePublished - Mar 6 2012

Keywords

  • Inflammation
  • Macrophage

ASJC Scopus subject areas

  • General

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    Ravishankar, B., Liu, H., Shinde, R., Chandler, P., Baban, B., Tanaka, M., Munn, D. H., Mellor, A. L., Karlsson, M. C. I., & McGaha, T. L. (2012). Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proceedings of the National Academy of Sciences of the United States of America, 109(10), 3909-3914. https://doi.org/10.1073/pnas.1117736109