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The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis through a Nonenzymatic Mechanism

Lauren M. F. Merlo, Weidan Peng, James B. DuHadaway, James D. Montgomery, George C. Prendergast, Alexander J. Muller and Laura Mandik-Nayak
J Immunol February 1, 2022, 208 (3) 571-581; DOI: https://doi.org/10.4049/jimmunol.2100705
Lauren M. F. Merlo
*Lankenau Institute for Medical Research, Wynnewood, PA;
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Weidan Peng
*Lankenau Institute for Medical Research, Wynnewood, PA;
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James B. DuHadaway
*Lankenau Institute for Medical Research, Wynnewood, PA;
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James D. Montgomery
*Lankenau Institute for Medical Research, Wynnewood, PA;
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George C. Prendergast
*Lankenau Institute for Medical Research, Wynnewood, PA;
†Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA; and
‡Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
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Alexander J. Muller
*Lankenau Institute for Medical Research, Wynnewood, PA;
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Laura Mandik-Nayak
*Lankenau Institute for Medical Research, Wynnewood, PA;
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Key Points

  • IDO2 has both enzymatic and nonenzymatic functions.

  • IDO2 mediates autoimmune arthritis via a nonenzymatic mechanism.

Abstract

IDO2 is one of two closely related tryptophan catabolizing enzymes induced under inflammatory conditions. In contrast to the immunoregulatory role defined for IDO1 in cancer models, IDO2 has a proinflammatory function in models of autoimmunity and contact hypersensitivity. In humans, two common single-nucleotide polymorphisms have been identified that severely impair IDO2 enzymatic function, such that <25% of individuals express IDO2 with full catalytic potential. This, together with IDO2’s relatively weak enzymatic activity, suggests that IDO2 may have a role outside of its function in tryptophan catabolism. To determine whether the enzymatic activity of IDO2 is required for its proinflammatory function, we used newly generated catalytically inactive IDO2 knock-in mice together with established models of contact hypersensitivity and autoimmune arthritis. Contact hypersensitivity was attenuated in catalytically inactive IDO2 knock-in mice. In contrast, induction of autoimmune arthritis was unaffected by the absence of IDO2 enzymatic activity. In pursuing this nonenzymatic IDO2 function, we identified GAPDH, Runx1, RANbp10, and Mgea5 as IDO2-binding proteins that do not interact with IDO1, implicating them as potential mediators of IDO2-specific function. Taken together, our findings identify a novel function for IDO2, independent of its tryptophan catabolizing activity, and suggest that this nonenzymatic function could involve multiple signaling pathways. These data show that the enzymatic activity of IDO2 is required only for some inflammatory immune responses and provide, to our knowledge, the first evidence of a nonenzymatic role for IDO2 in mediating autoimmune disease.

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Footnotes

  • This work was supported in part by the Giorgi Family Foundation (to L.M.-N.), the Zuckermann Autoimmune Disorder Research Fund (to L.M.-N.), and the National Cancer Institute of the National Institutes of Health under Award R01CA191191 (to G.C.P.).

  • Abbreviations used in this article

    ASC
    Ab-secreting cell
    CHS
    contact hypersensitivity
    GPI
    glucose-6-phosphate isomerase
    IP
    immunoprecipitation
    KI
    knock-in
    KO
    knockout
    kyn
    N-formylkynurenine
    LN
    lymph node
    Mgea5
    meningioma expressed antigen 5
    mIDO2
    murine IDO2
    O-GlcNAc
    O-linked β-N-acetyl-d-glucosamine
    PK
    pyruvate kinase
    RANbp10
    RAN binding protein 10
    Runx1
    Runt-related transcription factor 1
    SNP
    single-nucleotide polymorphism
    WT
    wild-type.

  • Received July 16, 2021.
  • Accepted November 15, 2021.
  • Copyright © 2022 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 208 (3)
The Journal of Immunology
Vol. 208, Issue 3
1 Feb 2022
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The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis through a Nonenzymatic Mechanism
Lauren M. F. Merlo, Weidan Peng, James B. DuHadaway, James D. Montgomery, George C. Prendergast, Alexander J. Muller, Laura Mandik-Nayak
The Journal of Immunology February 1, 2022, 208 (3) 571-581; DOI: 10.4049/jimmunol.2100705

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The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis through a Nonenzymatic Mechanism
Lauren M. F. Merlo, Weidan Peng, James B. DuHadaway, James D. Montgomery, George C. Prendergast, Alexander J. Muller, Laura Mandik-Nayak
The Journal of Immunology February 1, 2022, 208 (3) 571-581; DOI: 10.4049/jimmunol.2100705
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