DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling.
DNMT and HDAC inhibitors together abrogate endotoxemia mediated macrophage death by STAT3-JMJD3 signaling.
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DOI：
10.1016/j.biocel.2018.07.002
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Rajasingh J
中科院分区：
文献类型：
--
作者：
Samanta S;Zhou Z;Rajasingh S;Panda A;Sampath V;Rajasingh J
急性肺损伤(ALI)是脓毒症的常见并发症，在缺乏有效治疗的情况下常导致致命的肺部疾病。众所周知，骨髓来源的巨噬细胞在化解炎症和维持组织内稳态方面起着重要作用。在此，我们假设DNA甲基转移酶抑制剂(DNMTi)5-氮杂2-脱氧胞苷(Aza)和组蛋白脱乙酰酶抑制剂(HDACi)曲古抑素A(TSA)联合治疗对内毒素血症所致ALI的炎症诱导的下垂和细胞凋亡有缓解作用。为了验证这一假说，用亚致死剂量的脂多糖挑战小鼠，然后用单剂量的氮杂和TSA在腹膜内治疗一小时后，小鼠的细胞凋亡和炎症表现出显著的减轻。重要的是，我们观察到与单独使用两种药物相比，Aza和TSA联合治疗的LPS诱导的BMDM线粒体膜结构发生了显著的变化，DNA片段化程度降低，凋亡基因和焦磷酸酶基因的转录和翻译表达减少。这种保护作用是通过抑制JNK-ERK和STAT3-JMJD3激活途径实现的。因此，联合应用Aza和TSA靶向这些重要的信号通路将是治疗ALI的一种很好的方法。提出了Aza和TSA联合治疗对内毒素血症诱导的巨噬细胞凋亡和下垂的保护作用的分子机制。在骨髓来源的巨噬细胞(BMDM)中，内毒素通过MEK/MAP激活JMJD3-STAT3信号通路。此外，脂多糖增加JMJD3的表达可诱导促炎细胞因子的产生，从而导致细胞的凋亡。然而，表观遗传修饰剂Aza和TSA可以抑制MAPK、JMJD3-STAT3信号通路的活性，恢复线粒体膜的完整性，从而逆转内毒素诱导的BMDM的凋亡和下垂。
Acute lung injury (ALI) is a common complication of sepsis that often leads to fatal lung disease without effective therapies. It is known that bone marrow derived macrophages are important in resolving the inflammation and maintaining tissue homeostasis. Here, we hypothesize that treatment in combination of DNA methyl transferase inhibitor (DNMTi) 5-Aza 2-deoxycytidine (Aza) and histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) mitigates the inflammation induced pyroptosis and apoptosis during endotoxemia induced ALI. To test this hypothesis, the mice challenged with a sublethal dose of LPS followed by one-hour post-treatment with a single dose of Aza and TSA intraperitoneally showed a substantial attenuation of apoptosis and inflammation. Importantly, we observed significant changes in the mitochondrial membrane structure, and lower levels of DNA fragmentation, reduced expression of apoptotic and pyroptotic genes both transcriptionally and translationally in LPS induced BMDMs treated by a combination of Aza and TSA than in LPS-induced BMDMs treated with either drug alone. The protection was mediated by an inhibition of JNK-ERK and STAT3-JMJD3 activated pathways. Thus, targeting these important signaling pathways with the combination of Aza and TSA would be a good treatment modality for ALI. Proposed molecular mechanisms of the combination Aza and TSA treatment mediated protection on endotoxemia induced macrophage apoptosis and pyroptosis. In bone maroow derived macrophages (BMDMs), LPS activates JMJD3- STAT3 signaling pathway by MEK/MAP kinases. Moreover, the increase of JMJD3 by LPS induces pro-inflammatory cytokines, and result in apoptosis of the cells. However, epigenetic modifiers Aza and TSA, which inhibits the activity of MAPK, JMJD3-STAT3 signaling and restores mitochondrial membrane integrity, and thereby reverses the apoptosis and pyroptosis of BMDMs induced by LPS.
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DOI：
10.1016/j.jss.2011.06.007
发表时间：
2012-07
期刊：
The Journal of surgical research
影响因子：
--
作者：
Kochanek AR;Fukudome EY;Li Y;Smith EJ;Liu B;Velmahos GC;deMoya M;King D;Alam HB
通讯作者：
Alam HB
Toll 样受体在小胶质细胞长期激活过程中促进核转录因子核因子的线粒体易位
影响因子：
5.3
作者：
Ma, Bo;Yu, Jia;Cai, Huaibin
通讯作者：
Cai, Huaibin
影响因子：
64.8
作者：
Chang, LF;Karin, M
通讯作者：
Karin, M
影响因子：
15.9
作者：
Cheng, Kwong Tai;Xiong, Shiqin;Malik, Asrar B.
通讯作者：
Malik, Asrar B.
影响因子：
4.7
作者：
Bonora M;Pinton P
通讯作者：
Pinton P