Selective Biological Responses of Phagocytes and Lungs to Purified Histones.
Selective Biological Responses of Phagocytes and Lungs to Purified Histones.
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DOI：
10.1159/000452951
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发表时间：
2017
影响因子：
5.3
通讯作者：
Ward PA
中科院分区：
文献类型：
--
作者：
Fattahi F;Grailer JJ;Lu H;Dick RS;Parlett M;Zetoune FS;Nuñez G;Ward PA
组蛋白在许多不同的器官和细胞中引发强烈的促炎反应。我们使用人和小鼠的吞噬细胞和小鼠的肺来评估对纯化或重组组蛋白的生物学反应。H1在体外诱导细胞肿胀的能力最强，与Toll样受体(TLRs)2或4的需求无关。这些反应也与乳酸脱氢酶的释放有关。H_3和H_2B是诱导吞噬细胞内[Ca~(2+)]i升高的最强诱导剂。小鼠和人的吞噬细胞释放细胞因子和趋化因子主要是H_2A和H_2B的作用。双TLR2和TLR4基因敲除小鼠显著减少了单独暴露于组蛋白的巨噬细胞中诱导的细胞因子释放。相比之下，单个TLR-KO小鼠的巨噬细胞对细胞因子的产生几乎没有抑制作用。使用NLRP3炎症体方案，成熟的IL-1β的释放是H1的主要特征。组蛋白呼吸道给药所致的急性肺损伤提示，H1、H_2A和H_2B与肺泡白蛋白漏出、中性粒细胞聚集以及趋化因子和细胞因子向支气管肺泡液释放有关。这些结果表明，在炎症生物学和TLR2和TLR4需求的背景下，个体组蛋白具有不同的生物学作用。
Histones invoke strong proinflammatory responses in many different organs and cells. We assessed biological responses to purified or recombinant histones, using human and murine phagocytes and mouse lungs. H1 had the strongest ability in vitro to induce cell swelling independent of requirements for toll-like receptors (TLRs) 2 or 4. These responses were also associated with lactate dehydrogenase release. H3 and H2B were the strongest inducers of [Ca2+]i elevations in phagocytes. Cytokine and chemokine release from mouse and human phagocytes was predominately a function of H2A and H2B. Double TLR2 and TLR4 knockout mice had dramatically reduced cytokine release induced in macrophages exposed to individual histones. In contrast, macrophages from single TLR-KO mice showed few inhibitory effects on cytokine production. Using the NLRP3 inflammasome protocol, release of mature IL-1β was a feature of H1 predominantly. Acute lung injury following airway delivery of histones suggested that H1, H2A and H2B were linked to alveolar leak of albumin and buildup of PMNs as well as release of chemokines and cytokines into bronchoalveolar fluids. These results demonstrate distinct biological roles for individual histones in the context of inflammation biology and requirement of both TLR2 and TLR4.