Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death
Externalized histone H4 orchestrates chronic inflammation by inducing lytic cell death
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DOI：
10.1038/s41586-019-1167-6
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发表时间：
2019-05-09
期刊：
影响因子：
64.8
通讯作者：
Soehnlein, Oliver
中科院分区：
文献类型：
--
作者：
Silvestre-Roig, Carlos;Braster, Quinte;Soehnlein, Oliver
炎症的持续存在是造成全球医疗负担的重要病理生理因素。慢性炎症是由非程序性细胞死亡促进的(1，)(2)；然而，炎症是如何引发的，其细胞和分子介质及其治疗价值尚不清楚。在这里，我们使用动脉粥样硬化的小鼠模型--全球死亡的主要潜在原因--来证明细胞外组蛋白H4介导的平滑肌细胞(SMCs)的膜溶解触发动脉组织损伤和炎症。我们发现，激活的皮损SMC吸引中性粒细胞，触发含有核蛋白的中性粒细胞胞外陷阱的排出。其中，组蛋白H4与SMC结合并溶解，导致斑块失稳；反之，组蛋白H4的中和可防止SMC细胞死亡，稳定动脉粥样硬化病变。我们的数据确定了一种在慢性血管疾病的核心发现的细胞死亡形式，这种死亡是由白细胞引发的，可以作为治疗的靶点。
The perpetuation of inflammation is an important pathophysiological contributor to the global medical burden. Chronic inflammation is promoted by non-programmed cell death(1,)(2); however, how inflammation is instigated, its cellular and molecular mediators, and its therapeutic value are poorly defined. Here we use mouse models of atherosclerosis-a major underlying cause of mortality worldwide-to demonstrate that extracellular histone H4-mediated membrane lysis of smooth muscle cells (SMCs) triggers arterial tissue damage and inflammation. We show that activated lesional SMCs attract neutrophils, triggering the ejection of neutrophil extracellular traps that contain nuclear proteins. Among them, histone H4 binds to and lyses SMCs, leading to the destabilization of plaques; conversely, the neutralization of histone H4 prevents cell death of SMCs and stabilizes atherosclerotic lesions. Our data identify a form of cell death found at the core of chronic vascular disease that is instigated by leukocytes and can be targeted therapeutically.