Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α
Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α
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DOI：
10.1073/pnas.1116848108
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发表时间：
2011-12-20
影响因子：
11.1
通讯作者：
Kaplanski, Gilles
中科院分区：
文献类型：
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作者：
Berda-Haddad, Yael;Robert, Stephane;Kaplanski, Gilles
由细胞死亡引发的无菌性炎症是由于通常无活性且被隔离在细胞内的细胞内容物的释放；死亡细胞的细胞膜碎片也会导致无菌性炎症。遭受应激诱导凋亡的内皮细胞会释放膜微粒，这些膜微粒成为促炎信号的载体。在此，我们表明应激激活的内皮细胞会释放两种不同的颗粒群：一种颗粒群由膜微粒（<1μm，膜联蛋白V阳性，无DNA且无组蛋白）组成，另一种是更大的（1 - 3μm）含核碎片和组蛋白的类似凋亡小体的颗粒，代表凋亡小体。与现有概念相反，内皮微粒不含白细胞介素 - 1α，在体外也不诱导中性粒细胞趋化因子。相比之下，大的凋亡小体包含全长白细胞介素 - 1α前体以及加工后的成熟形式。在体外，这些凋亡小体以白细胞介素 - 1α依赖但白细胞介素 - 1β非依赖的方式诱导单核细胞趋化蛋白 - 1和白细胞介素 - 8趋化因子的分泌。将这些凋亡小体注射到小鼠腹腔会导致血清中性粒细胞诱导趋化因子升高，而白细胞介素 - 1受体拮抗剂共同处理可阻止这种情况。一致地，将这些大的凋亡小体注射到腹腔会诱导中性粒细胞浸润，白细胞介素 - 1阻断可阻止这种浸润。尽管凋亡通常被认为是非炎症性的，但这些数据表明未被吞噬的内皮凋亡小体是有炎症性的，为白细胞介素 - 1α提供了载体，因此构成了无菌性炎症的一种独特机制。
Sterile inflammation resulting from cell death is due to the release of cell contents normally inactive and sequestered within the cell; fragments of cell membranes from dying cells also contribute to sterile inflammation. Endothelial cells undergoing stress-induced apoptosis release membrane microparticles, which become vehicles for proinflammatory signals. Here, we show that stress-activated endothelial cells release two distinct populations of particles: One population consists of membrane microparticles (< 1 mu m, annexin V positive without DNA and no histones) and another larger (1-3 mu m) apoptotic body-like particles containing nuclear fragments and histones, representing apoptotic bodies. Contrary to present concepts, endothelial microparticles do not contain IL-1 alpha and do not induce neutrophilic chemokines in vitro. In contrast, the large apoptotic bodies contain the full-length IL-1 alpha precursor and the processed mature form. In vitro, these apoptotic bodies induce monocyte chemotactic protein-1 and IL-8 chemokine secretion in an IL-1 alpha-dependent but IL-1 beta-independent fashion. Injection of these apoptotic bodies into the peritoneal cavity of mice induces elevated serum neutrophil-inducing chemokines, which was prevented by cotreatment with the IL-1 receptor antagonist. Consistently, injection of these large apoptotic bodies into the peritoneal cavity induced a neutrophilic infiltration that was prevented by IL-1 blockade. Although apoptosis is ordinarily considered noninflammatory, these data demonstrate that nonphagocytosed endothelial apoptotic bodies are inflammatory, providing a vehicle for IL-1 alpha and, therefore, constitute a unique mechanism for sterile inflammation.