IDO2 mediates inflammatory responses through both enzymatic and non-enzymatic mechanisms

Abstract

Abstract The tryptophan catabolizing enzymes indoleamine-2,3-dioxygenase (IDO)1 and IDO2 play important immune modulatory roles in development of inflammation and tolerance. In contrast to the immune regulatory function described for IDO1, IDO2 is a proinflammatory modifier of disease in models of autoimmune arthritis and contact hypersensitivity. Using catalytically inactive IDO2 knock-in mice, we found that the enzymatic function of IDO2 was required to mediate inflammation in contact hypersensitivity but was not required for the development of autoimmunity, suggesting IDO2 acts through both enzymatic and non-enzymatic mechanisms depending on the immune context. Mechanistic studies identified the transcription factor Runx1 as a protein that directly binds to IDO2. The IDO2-Runx1 interaction is blocked by a therapeutic IDO2 monoclonal antibody, implicating Runx1 as a potential downstream mediator of IDO2 function. Runx1 has been shown to directly activate/repress genes involved in B cell activation and differentiation and indirectly affect transcription by inhibition of the NFκB pathway. Preliminary studies using luciferase reporter assays show that IDO2 does not affect Runx1’s direct transcriptional activity, suggesting that the downstream non-enzymatic IDO2 pathway is mediated by Runx1 indirect transcriptional regulation. Taken together, these data demonstrate IDO2 modulates inflammatory immune responses using both its enzymatic function and a non-enzymatic Runx1-mediated pathway.