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

99 Citations (Scopus)

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

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Autoantigens
Pathology
Self Tolerance
Adaptive Immunity
Autoimmunity
Innate Immunity
Tryptophan
Autoimmune Diseases
Disease Progression
Homeostasis
Cytokines
T-Lymphocytes
Kidney
Antigens
Mortality
DNA

Keywords

  • Inflammation
  • Macrophage

ASJC Scopus subject areas

  • General

Cite this

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. / Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul; Chandler, Phillip; Baban, Babak; Tanaka, Masato; Munn, David H.; Mellor, Andrew L.; Karlsson, Mikael C I; McGaha, Tracy L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 10, 06.03.2012, p. 3909-3914.

Research output: Contribution to journalArticle

Ravishankar, B, Liu, H, Shinde, R, Chandler, P, Baban, B, Tanaka, M, Munn, DH, Mellor, AL, Karlsson, MCI & McGaha, TL 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, vol. 109, no. 10, pp. 3909-3914. https://doi.org/10.1073/pnas.1117736109
Ravishankar, Buvana ; Liu, Haiyun ; Shinde, Rahul ; Chandler, Phillip ; Baban, Babak ; Tanaka, Masato ; Munn, David H. ; Mellor, Andrew L. ; Karlsson, Mikael C I ; McGaha, Tracy L. / Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 10. pp. 3909-3914.
@article{878adbb2927c47d8ade92fe89f160cfd,
title = "Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase",
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.",
keywords = "Inflammation, Macrophage",
author = "Buvana Ravishankar and Haiyun Liu and Rahul Shinde and Phillip Chandler and Babak Baban and Masato Tanaka and Munn, {David H.} and Mellor, {Andrew L.} and Karlsson, {Mikael C I} and McGaha, {Tracy L.}",
year = "2012",
month = "3",
day = "6",
doi = "10.1073/pnas.1117736109",
language = "English (US)",
volume = "109",
pages = "3909--3914",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "10",

}

TY - JOUR

T1 - Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

AU - Ravishankar, Buvana

AU - Liu, Haiyun

AU - Shinde, Rahul

AU - Chandler, Phillip

AU - Baban, Babak

AU - Tanaka, Masato

AU - Munn, David H.

AU - Mellor, Andrew L.

AU - Karlsson, Mikael C I

AU - McGaha, Tracy L.

PY - 2012/3/6

Y1 - 2012/3/6

N2 - 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.

AB - 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.

KW - Inflammation

KW - Macrophage

UR - http://www.scopus.com/inward/record.url?scp=84863231381&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863231381&partnerID=8YFLogxK

U2 - 10.1073/pnas.1117736109

DO - 10.1073/pnas.1117736109

M3 - Article

VL - 109

SP - 3909

EP - 3914

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 10

ER -