IDO2 Drives Autoantibody Production and Joint Inflammation in a Preclinical Model of Arthritis by Repressing Runx1...

The immunomodulatory enzyme IDO2 is an essential mediator of autoantibody production and joint inflammation in preclinical models of autoimmune arthritis. Although originally identified as a tryptophan-catabolizing enzyme, we recently discovered a previously unknown nonenzymatic pathway is essential for the proarthritic function of IDO2. We subsequently identified Runx1 (Runt-related transcription factor 1) as a potential component of the nonenzymatic pathway IDO2 uses to drive arthritis. In this study, we find that IDO2 directly binds Runx1 and inhibits its localization to the nucleus, implicating Runx1 as a downstream component of IDO2 function. To directly test whether Runx1 mediates the downstream pathway driving B cell activation in arthritis, we bred B cell conditional Runx1-deficient (CD19cre Runx1flox/flox) mice onto the KRN.g7 arthritis model in the presence or absence of IDO2. Runx1 loss did not affect arthritis in the presence of IDO2; however, deleting Runx1 reversed the antiarthritic effect of IDO2 loss in this model. Further studies demonstrated that the IDO2-Runx1 interaction could be blocked with a therapeutic anti-IDO2 mAb in vitro and that Runx1 was required for IDO2 Ig's therapeutic effect in vivo. Taken together, these data demonstrate that IDO2 mediates autoantibody production and joint inflammation by acting as a repressor of Runx1 function in B cells and implicate therapeutic targeting of IDO2-Runx1 binding as a strategy to inhibit autoimmune arthritis and other autoantibody-mediated diseases.