Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis

Psoriasis is a chronic and incurable skin disorder that causes inflammation. There is an urgent clinical need for new treatments. We identified the natural compound indirubin as a potential potent agent for the treatment of psoriasis, but it's therapeutic effect and underlying mechanisms were not well understood. Peripheral blood and skin tissues from psoriasis patients and healthy individuals were collected. Bioinformatics analysis was performed to investigate LAT1 expression and associated signal pathways in psoriasis skin lesions. A mouse model of psoriasis was established. Indirubin was administered separately or in combination with MDSCs depletion or adoptively transferred MDSCs. JPH203, rapamycin, siRNA, and NV5138 were further used to investigate the potential mechanism by which indirubin regulates MDSCs. Psoriasis patients had increased numbers of MDSCs in their blood and skin lesions, with high expression of Lat1. The upregulation of LAT1 expression and the arginine synthesis pathway was observed in psoriasis skin lesions. The number of MDSCs was increased, while their inhibitory effect on psoriatic T cells was decreased. Indirubin decreased Lat1 expression on the surface of MDSCs, inhibited mTOR pathway activation, upregulated Arg1 expression in MDSCs, and enhanced the immunosuppressive activity of MDSCs while inhibiting CD4+CCR6+ T cells. This study demonstrates indirubin's pharmacological and therapeutic effects, providing a basis for future clinical application in treating psoriasis.