Center of Experimental & Molecular Medicine, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Cells. 2021 Dec 28;11(1):82. doi: 10.3390/cells11010082.
Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during induced peritonitis. LPS induced expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient () mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the promoter was not altered by Tet2 deficiency. mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of mice after in vivo intraperitoneal infection. mice displayed enhanced bacterial growth during peritonitis, which was associated with a reduced capacity of peritoneal macrophages to inhibit the growth of in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during infection.
Tet 甲基胞嘧啶双加氧酶 2（Tet2）介导 DNA 的去甲基化。我们在此试图确定 Tet2 在脂多糖（LPS）暴露时在巨噬细胞中的表达和功能，以及在 LPS 诱导的肺和腹膜炎症以及期间的宿主反应中的表达和功能。LPS 在体外诱导小鼠巨噬细胞和人单核细胞以及体内支气管内滴注后诱导人肺泡巨噬细胞的表达。骨髓来源的髓样 Tet2 缺陷（）小鼠的巨噬细胞在受到几种 Toll 样受体激动剂刺激时显示出更高的 IL-1β、IL-6 和 CXCL1 产生；用 LPS 刺激肺泡和腹膜巨噬细胞也得到了类似的结果。组蛋白去乙酰化参与了 Tet2 对 IL-6 产生的影响，而 Tet2 缺乏并未改变 启动子处的甲基化。LPS 鼻内和腹腔内给药后，小鼠的支气管肺泡灌洗液和腹腔灌洗液中 IL-6 和 TNF 水平更高，而其他炎症反应没有改变。Tet2 缺陷的腹膜巨噬细胞在体内腹腔感染后产生更强的 IL-1β 和 IL-6，但在 小鼠的腹膜灌洗液中没有。在期间腹膜炎中，小鼠显示出更强的细菌生长，这与 腹膜巨噬细胞抑制体外生长的能力降低有关。总的来说，这些数据表明 Tet2 参与了 LPS 触发的巨噬细胞功能的调节以及期间的感染。
