Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 23, Issue 3, Pages 1885-1898Publisher
WILEY
DOI: 10.1111/jcmm.14089
Keywords
effector T cells; immune thrombocytopenia; programmed cell-death 1; regulatory T cells
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Funding
- Leading research group of scientific innovation, Major Research Plan of National Natural Science Foundation of China [91442204]
- Natural Science Foundation of Shandong Province [ZR2017PH022, ZR2017PH041]
- Taishan Scholar of Shandong Province
- Major Research Plan of Natural Science Foundation of Shandong Province [ZR2016QZ008]
- National Natural Science Foundation of China [81470284, 81500094, 81570103, 81600091, 81700113, 81770114, 81770133]
- State Key Clinical Specialty of China for Haematological Diseases
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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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