IDO2 Is a Critical Mediator of Autoantibody Production and Inflammatory Pathogenesis in a Mouse Model of Autoimmune Arthritis

Abstract

Rheumatoid arthritis (RA) and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme indoleamine-2,3-dioxygenase (IDO). However, the precise contributions of IDO function to autoimmunity remain unclear. Here, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of RA. We find that IDO2, not IDO1, is critical for arthritis development, providing the first direct evidence of separate in vivo functions for IDO1 and IDO2. Mice null for Ido2 display decreased joint inflammation relative to wild-type mice due to a reduction in pathogenic autoantibodies and antibody secreting cells. Notably, IDO2 appears to specifically mediate autoreactive, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 ko mice are able to mount productive antibody responses to model antigens in vitro and in vivo. Reciprocal adoptive transfer studies confirm that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Taken together, our results provide the first insights into IDO2 function by defining its pathogenic contributions to autoantibody-mediated autoimmunity.

Role of indoleamine 2,3-dioxygenase in health and disease

“…These enzymes are capable of exhibiting similar [23,24,35], opposing [37,38] or co-operative [25] biological actions. Furthermore, although it is clear that targeting IDO1 activity with the D-or L-isomers of 1-MT underlies the ability of the drug to modulate numerous physiological and pathophysiological conditions in experimental animals, questions regarding the specificity of 1-MT (and other IDO1-targeted small-molecule inhibitors) for IDO1 compared with IDO2 both in vitro and in vivo remain to be clarified.…”

“…These data suggest differential and non-redundant functions of IDO2 in vivo that are only now beginning to be revealed. For instance, recent data support the suggestion that IDO2, but not IDO1, is linked to the pathogenesis of arthritis in mice by promoting the production of autoantibodies [37], whereas, unlike IDO1, IDO2 is not involved in the progression of inflammatory skin cancer in a mouse model [38]. Despite this discrepancy in the roles of IDO1 and IDO2, IDO2 can act similarly to IDO1 in promoting the generation of immunosuppressive Tregs (regulatory T-cells) and Ido1 and Ido2 gene-deficient mice both exhibit reduced skin-contact hypersensitivity responses [35,38].…”

“…For example, in vitro studies have found that 1-D-MT inhibits cellular IDO2 activity [32], whereas evidence that 1-D-MT can target IDO2 in vivo derives from a very recent study employing Ido2 gene-deficient mice, which revealed a key role for IDO2 (but not IDO1) in supporting autoreactive antibody responses in a murine autoimmune arthritis model [37]. Other studies report that 1-L-MT is more effective as an IDO2 inhibitor than 1-D-MT [413,414] or conclude that both isomers of 1-MT are inefficient at inhibiting cellular IDO2 [414].…”

Tumoral Immune Resistance Mediated by Enzymes That Degrade Tryptophan

“…À/À mice show less severe inflammation of joints in a model of rheumatoid arthritis (36). These mice also have less intense hypersensitivity reactions and a reduced capacity to produce inflammatory cytokines and Tregs.…”

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“…In a rheumatoid arthritis inducible mouse model (KRN g7 B6), our institute has shown that deletion of the IDO2 gene alleviates arthritis [77]. IDO2 knockout (ko) KRN g7 mice were shown to have a significant delay in the onset of arthritis and an overall reduction in the amount of ankle swelling compared with KRN g7 and IDO1 ko KRN g7 mice.…”