Artesunate synergized dexamethasone in protecting intestinal barrier against acute graft-versus-host disease in a murine model

Background and Purpose: Acute graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation (HSCT). Gastrointestinal damage is a priority target of acute GVHD, presented as intestinal barrier dysfunction. The first-line treatment for acute GVHD is glucocorticoid, which, however, brings inevitable side effects. A search for alternative or supplementary therapy has been ongoing. Experimental Approach: Acute GVHD mice were treated with artesunate (ART), dexamethasone (DXM) or ART combined with DXM. The progression and severity of acute GVHD was evaluated by weight loss, clinical scores and survival. Intestinal permeability was assessed by FD-4 leakage. Colonic tissues were analyzed by qPCR, western blotting and staining techniques. Th17 and Treg cells were analyzed by flow cytometry. Key Results: ART alleviated acute GVHD and prolonged survival. Damages in intestinal tract, liver and skin of acute GVHD mice were evidently mitigated by ART. Tight junction proteins Claudin-1/3 were increased while Claudin-2 decreased in intestinal epithelium, intestinal epithelial cell renewal was accelerated, mucus lining the epithelium was thickened, and intestinal permeability was decreased in the ART-treated acute GVHD mice. ART induced allo-T cells to differentiate to Treg instead of Th17 through inhibiting mTOR pathway. Significantly, half-dose DXM combined with ART showed potent protective effect on intestinal barrier comparable to full-dose DXM did. Conclusion and Implications: ART ameliorated intestinal damages in acute GVHD mice through restoring tight junctions and Th17/Treg balance. Moreover, ART synergized DXM against immune attack on intestinal barrier, indicating ART could be a supplementary strategy that reduced DXM-related side effects.