Extracellular Histones Inhibit Efferocytosis
Extracellular Histones Inhibit Efferocytosis
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DOI：
10.2119/molmed.2012.00005
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发表时间：
2012-05-01
影响因子：
5.7
通讯作者：
Liu, Gang
中科院分区：
文献类型：
--
作者：
Friggeri, Arnaud;Banerjee, Sami;Liu, Gang
巨噬细胞和其他吞噬细胞对凋亡细胞的摄取和清除（称为巨噬细胞作用的过程）是炎症消退的主要组成部分。在急性炎症状态期间发现细胞外组蛋白浓度增加，并且似乎有助于器官系统功能障碍和死亡率。在这些研究中，我们研究了组蛋白在调节红细胞增多症中的潜在作用。我们发现，吞噬凋亡的中性粒细胞或胸腺细胞的巨噬细胞显着减少组蛋白H3或H4的存在下，但不是组蛋白H1。组蛋白H3表现出与巨噬细胞直接结合，这种作用通过将巨噬细胞与调理素生长抑制特异性基因6（Gas 6）和乳脂球-表皮生长因子（EGF）8（MFG-E8）预孵育而减弱。将组蛋白H3与可溶性α（V）β（5）整联蛋白和Mer孵育，但不与α（V）β（3）孵育，减少了其与巨噬细胞的结合。在组蛋白H3存在下，肺泡巨噬细胞对凋亡细胞的吞噬作用减弱。组蛋白H3与活化蛋白C的孵育。一种降解组蛋白的处理，在体外和体内条件下消除了其对红细胞增多症的抑制作用。目前的研究表明，细胞外组蛋白对炎症细胞有抑制作用，提示细胞外组蛋白参与急性炎症过程和组织损伤的新机制。在线地址：http://www.molmed.org doi：10.2119/molmed.2012.00005
The uptake and clearance of apoptotic cells by macrophages and other phagocytic cells, a process called efferocytosis, is a major component in the resolution of inflammation. Increased concentrations of extracellular histones are found during acute inflammatory states and appear to contribute to organ system dysfunction and mortality. In these studies, we examined the potential role of histones in modulating efferocytosis. We found that phagocytosis of apoptotic neutrophils or thymocytes by macrophages was significantly diminished in the presence of histones H3 or H4, but not histone H1. Histone H3 demonstrated direct binding to macrophages, an effect that was diminished by preincubation of macrophages with the opsonins growth arrest-specific gene 6 (Gas6) and milk fat globule-epidermal growth factor (EGF) 8 (MFG-E8). Incubation of histone H3 with soluble alpha(v)beta(5) integrin and Mer, but not with alpha(V)beta(3), diminished its binding to macrophages. Phagocytosis of apoptotic cells by alveolar macrophages in vivo was diminished in the presence of histone H3. Incubation of histone H3 with activated protein C. a treatment that degrades histones, abrogated its inhibitory effects on efferocytosis under both in vitro and in vivo conditions. The present studies demonstrate that histones have inhibitory effects on efferocytosis, suggesting a new mechanism by which extracellular histones contribute to acute inflammatory processes and tissue injury. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00005