Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s.
Highlights
It is an effective therapy to treat hematological disease, the benefit of allogeneic hematopoietic stem cell transplantation is limited by the induction of complications such as acute and chronic graft-versus-host disease (GVHD) [1, 2]
We hypothesized that enhanced regulated IRE-1a-dependent decay (RIDD) resulting from XBP-1s deletion is an important factor to reduce B cell pathogenicity in Chronic GVHD (cGVHD) development
We previously demonstrated that targeting XBP-1s in B cells efficiently prevented cGVHD by reducing activation and differentiation of B cells [24]
Summary
It is an effective therapy to treat hematological disease, the benefit of allogeneic hematopoietic stem cell transplantation (allo-HCT) is limited by the induction of complications such as acute and chronic graft-versus-host disease (GVHD) [1, 2]. The US Food and Drug Administration approved ibrutinib, a Bruton’s tyrosine kinase inhibitor, which is important for B cell receptor signaling, as second-line therapy of steroid-refractory cGVHD [11]. It shows that B cell regulation can be one of the essential targets for cGVHD treatment. We focus on the role of the unfolded protein response (UPR) mediators in regulating B cell activity after allo-HCT
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