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The Immunomodulatory Enzyme IDO2 Mediates Autoimmune Arthritis Through a Non-Enzymatic Mechanism
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 sing...
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Published in: | The Journal of immunology (1950) 2021-12, Vol.208 (3), p.571-581 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | 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 less than 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 if 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 non-enzymatic 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 this non-enzymatic 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 the first evidence of a non-enzymatic role for IDO2 in mediating autoimmune disease. |
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ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.2100705 |