Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.
Laboratory of Transcriptional Regulation, Institute of Medical Biology PAS, Lodowa 106, 93-232 Lodz, Poland.
Cells. 2021 Sep 18;10(9):2465. doi: 10.3390/cells10092465.
The increased level of hydrogen peroxide accompanies some modes of macrophage specification and is linked to ROS-based antimicrobial activity of these phagocytes. In this study, we show that activation of toll-like receptors with bacterial components such as LPS is accompanied by the decline in transcription of hydrogen peroxide decomposing enzyme-catalase, suppression of which facilitates the polarization of human macrophages towards the pro-inflammatory phenotype. The chromatin remodeling at the promoter involves LSD1 and HDAC1, but activity of the first enzyme defines abundance of the two proteins on chromatin, histone acetylation status and the transcription. LSD1 inhibition prior to macrophage activation with LPS prevents repression by enhancing the LSD1 and interfering with the HDAC1 recruitment to the gene promoter. The maintenance of catalase level with LSD1 inhibitors during M1 polarization considerably limits LPS-triggered expression of some pro-inflammatory cytokines and markers such as , , , , , and , but the effect of LSD1 inhibitors is lost upon catalase deficiency. Summarizing, activity of LSD1 allows for the repression in LPS stimulated macrophages, which negatively controls expression of some key pro-inflammatory markers. LSD1 inhibitors can be considered as possible immunosuppressive drugs capable of limiting macrophage M1 specialization.
过氧化氢水平的升高伴随着巨噬细胞特化的某些模式，并与这些吞噬细胞基于 ROS 的抗菌活性有关。在这项研究中，我们表明，用细菌成分（如 LPS）激活 Toll 样受体伴随着过氧化氢分解酶-过氧化氢酶转录的下降，抑制这种酶有利于人类巨噬细胞向促炎表型的极化。启动子处的染色质重塑涉及 LSD1 和 HDAC1，但第一酶的活性决定了两种蛋白质在染色质上的丰度、组蛋白乙酰化状态和转录。在 LPS 激活巨噬细胞之前抑制 LSD1 可通过增强 LSD1 并干扰 HDAC1 募集到基因启动子来防止 抑制。在 M1 极化过程中用 LSD1 抑制剂维持过氧化氢酶水平会极大地限制 LPS 触发的一些促炎细胞因子和标志物的表达，如 、 、 、 、 和 ，但在过氧化氢酶缺乏时，LSD1 抑制剂的作用会丧失。总之，LSD1 的活性允许在 LPS 刺激的巨噬细胞中进行 抑制，这负调控一些关键促炎标志物的表达。LSD1 抑制剂可以被认为是可能的免疫抑制药物，能够限制巨噬细胞 M1 特化。
