PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance.
PARP Traps Rescue the Pro-Inflammatory Response of Human Macrophages in the In Vitro Model of LPS-Induced Tolerance.
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DOI：
10.3390/ph14020170
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发表时间：
2021-02-22
期刊：
影响因子：
--
通讯作者：
Robaszkiewicz A
中科院分区：
文献类型：
--
作者：
Pietrzak J;Gronkowska K;Robaszkiewicz A
继发性感染引起败血症，导致患者残疾或死亡。巨噬细胞与细菌组分（如脂多糖-LPS）的接触激活Toll样受体（TLR）下游的细胞内信号传导途径，其启动免疫促炎反应。然而，核因子-κ B（NF-κB）依赖性促炎细胞因子的表达在单次高或多次LPS刺激后显著降低。已知聚（ADP-核糖）聚合酶-1（PARP 1）作为NF-κB的辅因子，我们的目的是验证PARP 1对LPS诱导的人巨噬细胞耐受性的发展可能贡献的假设。使用TNF-α mRNA表达作为读数，我们证明PARP 1与TNF-α启动子的相互作用控制巨噬细胞免疫麻痹。我们证实PARP 1从基因启动子中被挤出，而Olaparib预处理细胞可维持巨噬细胞对另一种LPS处理的反应性。此外，用蛋白酶体抑制剂MG 132预处理细胞完全消除了Olapari B的作用，表明PARP 1与NF-κB在相同的调节途径中起作用，其控制促炎细胞因子转录。在机制上，PARP 1捕获允许p65与LPS刺激的细胞中的TNF-α启动子重新结合。总之，PARP陷阱防止PARP 1在巨噬细胞刺激时从TNF-α启动子挤出，从而维持TLR激活的染色质反应性，允许p65和TNF-α转录的重新结合。
Secondary infections cause sepsis that lead to patient disability or death. Contact of macrophages with bacterial components (such as lipopolysaccharide—LPS) activates the intracellular signaling pathway downstream of Toll-like receptors (TLR), which initiate an immune proinflammatory response. However, the expression of nuclear factor-kappa B (NF-κB)-dependent proinflammatory cytokines significantly decreases after single high or multiple LPS stimulations. Knowing that poly(ADP-ribose) polymerase-1 (PARP1) serves as a cofactor of NF-κB, we aimed to verify a hypothesis of the possible contribution of PARP1 to the development of LPS-induced tolerance in human macrophages. Using TNF-α mRNA expression as a readout, we demonstrate that PARP1 interaction with the TNF-α promoter, controls macrophage immunoparalysis. We confirm that PARP1 is extruded from the gene promoter, whereas cell pretreatment with Olaparib maintains macrophage responsiveness to another LPS treatment. Furthermore, cell pretreatment with proteasome inhibitor MG132 completely abrogates the effect of Olaparib, suggesting that PARP1 acts with NF-κB in the same regulatory pathway, which controls pro-inflammatory cytokine transcription. Mechanistically, PARP1 trapping allows for the re-rebinding of p65 to the TNF-α promoter in LPS-stimulated cells. In conclusion, PARP traps prevent PARP1 extrusion from the TNF-α promoter upon macrophage stimulation, thereby maintaining chromatin responsiveness of TLR activation, allowing for the re-binding of p65 and TNF-α transcription.
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