Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation
Cellular senescence induced by S100A9 in mesenchymal stromal cells through NLRP3 inflammasome activation
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DOI：
10.18632/aging.102409
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发表时间：
2019-11-15
期刊：
影响因子：
5.2
通讯作者：
Chang, Chunkang
中科院分区：
文献类型：
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作者：
Shi, Lei;Zhao, Youshan;Chang, Chunkang
骨髓增生异常综合征（MDS）患者的骨髓基质细胞表现出衰老表型，但其潜在机制尚未阐明。恶性克隆和骨髓微环境中的促炎信号传导已被确定为 MDS 的关键发病驱动因素。我们的研究表明，S100A9 在低风险 MDS 中高表达。此外，正常原代间充质基质细胞（MSC）和人基质细胞系HS-27a与低风险MDS骨髓单核细胞共培养获得了衰老表型。外源补充的 S100A9 还诱导 MSC 和 HS-27a 细胞的细胞衰老。重要的是，Toll 样受体 4 (TLR4) 抑制或敲低可减弱 S100A9 诱导的细胞衰老。此外，我们发现 S100A9 诱导 NLRP3 炎性体形成和 IL-1 β 分泌； MDS 患者样本的研究结果进一步证实了这些想法。此外，ROS和IL-1β抑制抑制了S100A9诱导的细胞衰老，而NLRP3过表达和外源性IL-1β补充则诱导细胞衰老。我们的研究表明，S100A9 通过 TLR4、NLRP3 炎性体形成和 IL-1 β 分泌促进骨髓基质细胞的细胞衰老。我们的研究结果加深了对MSCs MDS 重编程分子机制的理解，并表明S100A9 在骨髓肿瘤-环境相互作用中的重要作用。
Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that S100A9 is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype. Exogenous supplemented S100A9 also induced cellular senescence in MSCs and HS-27a cells. Importantly, Toll-like receptor 4 (TLR4) inhibition or knockdown attenuated the cellular senescence induced by S100A9. Furthermore, we showed that S100A9 induces NLRP3 inflammasome formation, and IL-1 beta secretion; findings in samples from MDS patients further confirmed these thoughts. Moreover, ROS and IL-1 beta inhibition suppressed the cellular senescence induced by S100A9, whereas NLRP3 overexpression and exogenous IL-1 beta supplementation induces cellular senescence. Our study demonstrated that S100A9 promotes cellular senescence of bone marrow stromal cells via TLR4, NLRP3 inflammasome formation, and IL-1 beta secretion for its effects. Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of S100A9 in tumor-environment interactions in bone marrow.