Anti-inflammatory role of IDO and tryptophan metabolites

Inflammation is essential to the establishment of homeostasis following injury and inflammatory cell and the cytokine network associate with tissue repair. However, sometimes inflammation can cause further inflammation; it can become self-perpetuating. One of the many possibilities of prolonged secretion of cytokines and growth factor is autoimmunity and delay in wound closure. The current anti-inflammatory treatment modalities vary however their adverse effects are common. Here we asked the question of whether Kynurenine (Kyn), one of the tryptophan (Trp) metabolite, could modulate the inflammation by altering the profile of the key pro-inflammatory cytokines as well as the proliferation of immune cells. We showed that Kyn treatment significantly reduced some pro-inflammatory cytokines and chemokines such as IL-17, IL-2, CXCL-9 and CXCL-10 in ConA⁺ Kyn-treated splenocytes. To validate our findings in a wound healing model, we also showed that topical application of Kyn cream resulted in fewer infiltration of CD3⁺ T cells at wound site. Further, in this study we used kynurenic acid (KynA) instead of Kyn as KynA is the end product and safer metabolites in the kynurenine pathway. The emphasis was given in evaluating the effect of KynA on expression of IL-17/IL-23 axis which has recently been identified to be very important in the immunopathogenesis of autoimmune diseases and inflammation such as psoriasis. Our findings have shown that KynA can modulate the frequency of IL-23 and IL-17 by DCs and CD4⁺ cells. Moreover, we showed that KynA suppresses the production of IL-23 in DCs through GPCR35 activation. We then evaluated the therapeutic use of intra-lesional injection of IDO-expressing fibroblasts, as a source of Kyn and KynA production in psoriasis, which is one of the most common recurrent chronic inflammatory diseases of the skin. The findings of this work demonstrated that IDO-expressing cells significantly improved thickness, erythema, and scaling scores in skin psoriatic like condition. Moreover, IDO-expressing fibroblasts reduce infiltration of IL-17⁺ CD4⁺, IL-17⁺ γδ⁺ T cells, IL-23⁺-activated dendritic cells and granulocytes in skin psoriatic like condition. The findings presented in this thesis collectively prove the potent local immunosuppressive activity of IDO-expressing dermal fibroblast and tryptophan metabolites in skin inflammatory conditions.

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