Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype.
Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype.
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DOI：
10.3389/fonc.2016.00151
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发表时间：
2016
影响因子：
4.7
通讯作者：
List A
中科院分区：
文献类型：
--
作者：
Sallman DA;Cluzeau T;Basiorka AA;List A
骨髓增生异常综合征（MDS）的特征是在反复发生体细胞基因突变和染色体异常的情况下骨髓细胞学异常增殖和无效造血。从一系列不同的遗传异常中驱动共同临床表型的潜在致病机制直到最近才开始出现。越来越多的证据强调了先天免疫系统通过 NF-κB 激活上调炎症细胞因子在 MDS 发病机制中的不可或缺的作用。最近的研究表明，造血干细胞/祖细胞中 NLRP3 炎症小体的激活是 MDS 中的关键收敛信号，通过 caspase-1 成熟导致随后的克隆扩张和焦亡细胞死亡。具体来说，警报蛋白 S100A9 和/或创始基因突变通过活性氧的产生触发焦亡，导致氧化还原敏感的 NLRP3 炎性体和 β-连环蛋白的组装和激活，从而确保 MDS 克隆的繁殖。更重要的是，有针对性地抑制该途径中的各个步骤可以恢复有效的造血功能。总之，对焦亡在 MDS 患者临床表型中的作用的描述已经确定了新的治疗策略，为 MDS 的治疗提供了重要的希望。
Myelodysplastic syndromes (MDS) are characterized by bone marrow cytological dysplasia and ineffective hematopoiesis in the setting of recurrent somatic gene mutations and chromosomal abnormalities. The underlying pathogenic mechanisms that drive a common clinical phenotype from a diverse array of genetic abnormalities have only recently begun to emerge. Accumulating evidence has highlighted the integral role of the innate immune system in upregulating inflammatory cytokines via NF-κB activation in the pathogenesis of MDS. Recent investigations implicate activation of the NLRP3 inflammasome in hematopoietic stem/progenitor cells as a critical convergence signal in MDS with consequent clonal expansion and pyroptotic cell death though caspase-1 maturation. Specifically, the alarmin S100A9 and/or founder gene mutations trigger pyroptosis through the generation of reactive oxygen species leading to assembly and activation of the redox-sensitive NLRP3 inflammasome and β–catenin, assuring propagation of the MDS clone. More importantly, targeted inhibition of varied steps in this pathway restore effective hematopoiesis. Together, delineation of the role of pyroptosis in the clinical phenotype of MDS patients has identified novel therapeutic strategies that offer significant promise in the treatment of MDS.