Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.
Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.
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DOI：
10.1084/jem.20112615
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发表时间：
2013-07-01
期刊：
影响因子：
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通讯作者：
Minter LM
中科院分区：
文献类型：
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作者：
Roderick JE;Gonzalez-Perez G;Kuksin CA;Dongre A;Roberts ER;Srinivasan J;Andrzejewski C Jr;Fauq AH;Golde TE;Miele L;Minter LM
NOTCH1信号支持Th1细胞的促炎行为，与人类和小鼠再生障碍性贫血的发生有关。重型再生障碍性贫血(AA)是一种骨髓衰竭(BMF)疾病，常由造血祖细胞免疫功能异常破坏所致。虽然Th1介导的病理对于再生障碍性贫血有很好的描述，但驱动疾病进展的分子机制仍然不清楚。Notch信号通路在存在极化细胞因子的情况下介导Th1细胞的分化，这一作用需要通过γ分泌酶对Notch受体进行酶处理。利用小鼠再障模型，我们证明了在疾病活动期，调节Th1细胞分化的关键转录因子NOTCH1IC和T-BET在脾和骨髓浸润性T细胞中的表达均增加。有条件地删除Notch1或在体内应用γ分泌酶抑制物(GSI)可以减轻疾病，并将小鼠从致命的BMF中拯救出来。在未经治疗的再障患者外周T细胞中，NOTCH1IC显著升高，并与Tbx21启动子结合，表明NOTCH1直接调控T-BET编码基因。在体外用GSI处理患者细胞可降低NOTCH1IC水平，减少在Tbx21启动子可检测到的NOTCH1，并减少T-BET的表达，表明在疾病活动期间NOTCH1信号对GSI有反应。总体而言，这些结果确认Notch信号是Th1介导的再生障碍性贫血发病机制的主要驱动因素，并可能代表治疗干预的新靶点。
Notch1 signaling sustains the proinflammatory behavior of Th1 cells, implicated in the development of aplastic anemia in humans and mice. Severe aplastic anemia (AA) is a bone marrow (BM) failure (BMF) disease frequently caused by aberrant immune destruction of blood progenitors. Although a Th1-mediated pathology is well described for AA, molecular mechanisms driving disease progression remain ill defined. The NOTCH signaling pathway mediates Th1 cell differentiation in the presence of polarizing cytokines, an action requiring enzymatic processing of NOTCH receptors by γ-secretase. Using a mouse model of AA, we demonstrate that expression of both intracellular NOTCH1IC and T-BET, a key transcription factor regulating Th1 cell differentiation, was increased in spleen and BM-infiltrating T cells during active disease. Conditionally deleting Notch1 or administering γ-secretase inhibitors (GSIs) in vivo attenuated disease and rescued mice from lethal BMF. In peripheral T cells from patients with untreated AA, NOTCH1IC was significantly elevated and bound to the TBX21 promoter, showing NOTCH1 directly regulates the gene encoding T-BET. Treating patient cells with GSIs in vitro lowered NOTCH1IC levels, decreased NOTCH1 detectable at the TBX21 promoter, and decreased T-BET expression, indicating that NOTCH1 signaling is responsive to GSIs during active disease. Collectively, these results identify NOTCH signaling as a primary driver of Th1-mediated pathogenesis in AA and may represent a novel target for therapeutic intervention.