Histone H4 directly stimulates neutrophil activation through membrane permeabilization
Histone H4 directly stimulates neutrophil activation through membrane permeabilization
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DOI：
10.1002/jlb.3a0620-342r
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发表时间：
2020-08-17
影响因子：
5.5
通讯作者：
Hartshorn, Kevan L.
中科院分区：
文献类型：
--
作者：
Hsieh, I-Ni;Deluna, Xavier;Hartshorn, Kevan L.
细胞外组蛋白已被认为是多种疾病（包括败血症、肺和肝脏疾病）中组织炎性损伤的原因。然而，很少有人知道他们与中性粒细胞的相互作用，以及这可能有助于损伤。在这里，它表明，组蛋白H4作为中性粒细胞激活剂诱导过氧化氢的生产，脱粒，细胞粘附，和IL-8的产生。组蛋白H4引起中性粒细胞膜的透化（在其他细胞类型中描述的现象），导致加速的细胞死亡。H4引起中性粒细胞胞内钙持续升高，这是呼吸爆发激活和脱粒所必需的。在H4介导的活化中没有发现TLR或ATP受体的令人信服的证据。然而，百日咳毒素和渥曼青霉素（G蛋白和PI 3 K的抑制剂）抑制H4诱导的过氧化氢的产生和脱粒。这些研究表明，组蛋白H4在感染或炎症部位的释放可能增强中性粒细胞活化并促进额外的炎症反应。这些研究可能为开发新的治疗策略提供更好的基础，以阻断脓毒症和各种形式的肺损伤（包括流感或SAR-CoV 2等病毒引起的肺损伤）中的中性粒细胞胞外陷阱（NET）和H4相关病理。
Extracellular histones have been implicated as a cause of tissue inflammatory injury in a variety of disorders including sepsis, lung, and liver diseases. However, little is known about their interactions with neutrophils and how this might contribute to injury. Here, it is shown that histone H4 acts as neutrophil activator by inducing hydrogen peroxide production, degranulation, cell adhesion, and IL-8 generation. Histone H4 caused permeabilization of the neutrophil membrane (a phenomenon described in other cell types) leading to accelerated cell death. H4 caused sustained rise in neutrophil intracellular calcium that is necessary for respiratory burst activation and degranulation. Convincing evidence was not found for TLRs or ATP receptors in H4 mediated activation. However, pertussis toxin and wortmannin (inhibitors of G protein and PI3K) inhibited H4-induced hydrogen peroxide production and degranulation. These studies suggest that release of histone H4 in sites of infection or inflammation may potentiate neutrophil activation and promote additional inflammatory responses. These studies may provide a better basis for developing novel therapeutic strategies to block neutrophil extracellular trap (NET) and H4-related pathology in sepsis and various forms of lung injury including that induced by viruses like influenza or SAR-CoV2.