023 Global knockout of immunomodulatory indoleamine 2,3-dioxygenase has no effect on psoriasiform lesions in the imiquimod-induced mouse model of psoriasis

Indoleamine 2,3-dioxygenase (IDO) is a cytosolic rate-limiting immunomodulatory enzyme that degrades tryptophan, resulting in tryptophan depletion and the accumulation of metabolites. The expression/activity of IDO in various cells, such as macrophages, dendritic cells, and trophoblasts, has been demonstrated to block T cell responses in a number of situations, including towards allogeneic fetuses and grafts/transplants. IDO induces immune suppression through two non–mutually exclusive mechanisms: (1) IDO degrades tryptophan into kynurenine, thus depleting the microenvironment of this essential amino acid and ‘‘starving’’ immune cells and (2) the kynurenine produced by IDO is actively immune suppressive through mechanisms including the induction of regulatory T cells (Tregs) through binding to the aryl hydrocarbon receptor. We hypothesized that IDO knockout mice would exhibit a hyperactive immune response because of decreased Treg function and therefore an exacerbation of the psoriasiform phenotype in the imiquimod-induced mouse model of psoriasis, an immune-mediated skin disease. Littermate wild-type and IDO knockout mice were treated with imiquimod, and ear edema, the severity of skin lesions, and the thickness of the epidermis were monitored. Unexpectedly, imiquuimod-treated IDO knockout and wild-type mice exhibited a similar increase in ear edema, psoriasis area and severity index (PASI) scores, and epidermal thickness, indicating no effect of IDO gene loss on the skin’s response to imiquimod. While these data may suggest a lack of involvement of IDO and Tregs in skin inflammation, other possible mechanisms, such as compensatory changes or the possibility that imiquimod already maximally suppressed Treg function, must also be considered.