Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Hee-Jin Choi, Yongxia Wu, Brianyell McDaniel Mims, Allison Pugel, Chih-Hang Anthony Tang, Linlu Tian, Chih-Chi Andrew Hu, Xue-Zhong Yu
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Abstract

Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.

内质网应激反应介质 IRE-1α 促进宿主树突状细胞在移植物抗宿主疾病发展中的作用
异基因造血细胞移植是治疗血液系统恶性肿瘤的有效方法,但移植物抗宿主病(GVHD)等并发症会限制其治疗效果。移植前的调理方案,包括化疗或照射,会引发内质网应激。IRE-1α是一种主要的内质网应激介质,可进一步激活剪接XBP-1(XBP-1s)和调控IRE-1依赖性衰变(RIDD)。IRE-1α-XBP-1s信号传导控制着树突状细胞(DC)的分化和抗原呈递,这对GVHD的进展至关重要。在这项研究中,我们使用 DC 特异性 XBP-1 缺失的小鼠作为供体或受体,观察到 XBP-1s 在诱导 GVHD 的过程中对宿主 DC 至关重要,但对移植物抗白血病反应却无关紧要。为了特异性地靶向宿主体内的IRE-1α,我们在骨髓移植前用IRE-1α抑制剂B-I09处理受体小鼠3天,这能显著抑制GVHD的发生,同时维持移植物抗白血病效应。XBP-1缺陷或经BI09处理的受者在照射和骨髓移植后直流电存活率降低。抑制 IRE-1α 也会导致 DC 异体活性降低,进而减少异体 T 细胞的增殖和活化。通过使用 RIDD 缺失的 DC 进行进一步研究,我们观察到 RIDD 也是最佳 DC 激活所必需的。综上所述,XBP-1s 和 RIDD 都能促进宿主 DC 的存活和异活性,从而导致 GVHD 的发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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