Indirubin modulates CD4 + T-cell homeostasis via PD1/PTEN/AKT signalling pathway in immune thrombocytopenia.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE(2019)
摘要
Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by an immune mediated decrease in platelet number. Disturbance of CD4(+) T-cell homeostasis with simultaneous decrease of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) as well as unrestricted proliferation and activation of peripheral CD4(+) effector T cells underpin the pathophysiology of ITP. Indirubin is an active ingredient of a traditional Chinese herb called Indigofera tinctoria L. which is clinically used for the treatment of ITP patients. Whether indirubin targets the Tregs/effector T cell-axis to restore platelet number is unknown. In our in vitro studies, Indirubin could significantly enhance the number and function of Tregs and meanwhile dampen the activation of effector T cells in a dose-dependent manner. Indirubin was observed to restore the expression of programmed cell-death 1 (PD1) and phosphatase and tensin homolog (PTEN) on the CD4(+) T cells of ITP patients, leading to the subsequent attenuation of the AKT/mTOR pathway. Furthermore, these observations were recapitulated in an active murine model of ITP with a prominent platelet response. Thus, our results identified a potentially novel mechanism of the therapeutic action of indirubin in the treatment of ITP through regulating the homeostasis of CD4(+) T cells in a PD1/PTEN/AKT signalling pathway.
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关键词
effector T cells,immune thrombocytopenia,programmed cell-death 1,regulatory T cells
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