Loading…

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of immunology (1950) 2021-12, Vol.208 (3), p.571-581
Main Authors: Merlo, Lauren M.F., Peng, Weidan, DuHadaway, James B., Montgomery, James D., Prendergast, George C., Muller, Alexander J., Mandik-Nayak, Laura
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2100705