Glucocorticoids regulate thrombopoiesis by remodeling the megakaryocyte transcriptome

Abstract

Background and objectives

Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune thrombocytopenia. However, their efficacy and mechanisms of action in immune thrombocytopenia are not fully understood. This study investigates the mechanism of glucocorticoids actions on platelet production.

Methods and results

Dexamethasone reduced bleeding in mice and rapidly increased circulating young platelet counts. In vitro glucocorticoid treatment stimulated proplatelet formation by megakaryocytes and platelet like-particle release. This effect was blocked by glucocorticoid receptor (GR) antagonist RU486, indicating GR-dependent mechanism. Genome wide analysis revealed that dexamethasone regulates the expression of more than 1000 genes related to numerous cellular functions, including predominant cytoplasm and cytoskeleton reorganization. Dexamethasone and other glucocorticoids induced the expression of Gda (gene encoding guanine deaminase), which has been reported to have a role in dendrite development. Inhibition of guanine deaminase enzymatic activity blocked dexamethasone stimulation of proplatelet formation, implicating a critical role for this enzyme in glucocorticoid-mediated platelet production.

Conclusions

Our findings identify glucocorticoids as new regulators of thrombopoiesis.