ADAR1 improved Treg cell function through the miR-21b/Foxp3 axis and inhibits the progression of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Th17/Treg equilibrium towards the pro-inflammatory Th17 side contributes greatly to the rejection during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Forkhead box P3 (Foxp3) is important in the pathogenic conversion between Th17 and Treg cells. However, how Foxp3 expression was regulated is largely unknown. Here, we investigated the role of RNA-editing enzyme ADAR1 in Foxp3-mediated Th17/Treg imbal-ance and progression of acute graft-versus-host disease (aGVHD), a most serious complication in patients received allo-HSCT. Th1, Th17 and Treg cells were respectively isolated from peripheral blood CD4 + T cells of allo-HSCT patients, and we found that proportions of Th1 and Th17 were markedly increased, while Treg pro-portion was significantly decreased in aGVHD patients post transplantation compared with non-aGVHD patients, accompanied by decreased ADAR1 and increased miR-21b levels. RNA-immunoprecipitation (RIP) combined with gain-and loss-of-function experiments demonstrated that ADAR1 improved Treg cell functions and nega-tively regulated the production of miR-21b, a Foxp3-targeting miRNA. Inhibition of miR-21b improved Treg functions, and Foxp3 knockdown could eliminate the effect of miR-21b inhibition or ADAR1 overexpression on Treg function. Finally, an aGVHD mouse model was established and Ad-O/E-ADAR1 was injected into aGVHD mice to verify the effect of ADAR1 on aGVHD progression in vivo. The results showed that ADAR1 over-expression decreased Th17 proportion and increased Treg proportion in aGVHD mice and obviously improved tissue necrosis and reticular structure of aGVHD liver and lung in vivo. Collectively, ADAR1 suppresses miR-21b production and improves Foxp3-mediated Treg cell function to inhibit the progression of aGVHD after allo-HSCT.

Automated summary

Th17/Treg imbalance contributes to rejection in allo-HSCT. ADAR1 plays a critical role in regulating Foxp3 expression and improving Treg cell function by suppressing miR-21b production. In aGVHD mouse model, ADAR1 over-expression decreased Th17 proportion, increased Treg proportion, and improved tissue necrosis and reticular structure in liver and lung.