Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo.
Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo.
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DOI：
10.1371/journal.ppat.1005319
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发表时间：
2015-12
期刊：
影响因子：
6.7
通讯作者：
Herwald H
中科院分区：
文献类型：
--
作者：
Westman J;Papareddy P;Dahlgren MW;Chakrakodi B;Norrby-Teglund A;Smeds E;Linder A;Mörgelin M;Johansson-Lindbom B;Egesten A;Herwald H
先天免疫系统在很大程度上依赖于模式识别受体与病原体或损伤相关的分子模式分子的相互作用。细胞外组蛋白属于后一组，并且它们的释放已被描述为有助于诱导全身炎症反应。然而，很少有人知道他们的功能在早期免疫反应入侵病原体。在这里，我们发现细胞外组蛋白特异性靶向人血液中的单核细胞，这引起了这些细胞的趋化性趋化因子CXCL 9和CXCL 10的动员。趋化因子的诱导涉及单核细胞上的toll样受体4/髓样分化因子2复合物，并且受干扰素-γ的控制。因此，用细胞外组蛋白皮下激发导致小鼠气囊模型中CXCL 10水平升高，并且白细胞以TLR 4依赖性方式流入注射部位。当分析化脓性链球菌引起的坏死性筋膜炎患者的组织活检时，细胞外组蛋白H4和CXCL 10在坏死组织中免疫染色，但在健康组织中不染色。总的来说，这些结果首次表明，细胞外组蛋白具有作为化学引诱物的重要功能，因为它们的局部释放触发免疫细胞向感染部位的募集。细胞外组蛋白在病理条件下的有害作用最近引起了相当大的关注。然而，很少有人知道他们的功能，损伤相关的分子模式分子。我们的研究首次表明，细胞外组蛋白触发单核细胞趋化因子的诱导。由于这种相互作用依赖于模式识别受体，即Toll样受体4，我们的数据确实指出了细胞外组蛋白在危险信号传导中的重要作用。值得注意的是，CXCL 9和CXCL 10是化学引诱物，并且在皮下小鼠模型中免疫细胞向组蛋白注射部位的募集支持了低水平的细胞外组蛋白构成宿主应答的一部分的概念。
The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection. The detrimental effects of extracellular histones under pathological conditions have lately attracted considerable attention. However, little is known about their functions as damage-associated molecular pattern molecules. Our study shows for the first time that extracellular histones trigger the induction of chemotactic chemokines from monocytes. As this interaction is dependent on a pattern recognition receptor, namely toll-like receptor 4, our data indeed point to an important role of extracellular histones in danger signaling. Notably, CXCL9 and CXCL10 are chemoattractants, and the recruitment of immune cells to the site of histone injection in a subcutaneous mouse model supports the concept that low levels of extracellular histones constitute a part of the host response.