WITHDRAWN: Host SPHK1 deficiency ameliorates acute graft-versus-host disease by attenuating ER stress-induced gastrointestinal injury

Abstract

Graft-versus-host disease (GVHD) remains a major obstacle in successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that inhibiting sphingosine kinase 1 (SPHK1), an enzyme that phosphorylates sphingosine to bioactive sphingosine-1-phosphate (S1P), effectively ameliorates acute GVHD (aGVHD). The absence of SPHK1 in the host exerts a beneficial effect on maintaining gut homeostasis by limiting intestinal epithelial cell (IEC) injury, thus reducing gut permeability and preventing bacterial translocation, which in turn decreases the activation of antigen-presenting cells and T cell infiltration. Persistent ER stress is observed during GVHD in the gastrointestinal tract and contributes to IEC injury. SPHK1 deficiency attenuates IEC damage by alleviating ER stress, a process that can be reversed by supplementation with exogenous S1P. FTY720, an S1P receptor antagonist, significantly inhibits ER stress-induced IEC injury. Additionally, host SPHK1 deficiency helps in shaping the gut microbiota by diminishing the presence of MHC II inducer-associated bacteria, such as Lactobacillus murinus, and increasing the abundance of the IFN-γ suppressor Akkermansia muciniphila. This leads to decreased MHC II expression in IECs, contributing to an overall reduction in aGVHD severity. Together, our data reveal a pathogenic role of host SPHK1 in gastrointestinal injury during aGVHD.