Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α

被引:180
作者
Berda-Haddad, Yael [2 ]
Robert, Stephane [2 ,4 ]
Salers, Paul [2 ]
Zekraoui, Leila [3 ]
Farnarier, Catherine [2 ]
Dinarello, Charles A. [1 ]
Dignat-George, Francoise [2 ,4 ]
Kaplanski, Gilles [2 ,5 ]
机构
[1] Univ Colorado Denver, Div Infect Dis, Aurora, CO 80045 USA
[2] Aix Marseille Univ, Unite Mixte Rech 608, F-13005 Marseille, France
[3] Aix Marseille Univ, Ctr Explorat Physiopathol Avancees, F-13005 Marseille, France
[4] Hop Conception, Assistance Publ Hop Marseille, Hematol Lab, F-13005 Marseille, France
[5] Hop Conception, Assistance Publ Hop Marseille, Serv Med Interne, F-13005 Marseille, France
基金
美国国家卫生研究院;
关键词
ischemia/reperfusion; autoimmunity; lupus erythematosus; SYSTEMIC-LUPUS-ERYTHEMATOSUS; IMMUNE-RESPONSES; DYING CELLS; MICROPARTICLES; DEATH; IDENTIFICATION; IL-1-ALPHA; INDUCTION; SECRETION; NECROSIS;
D O I
10.1073/pnas.1116848108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:20684 / 20689
页数:6
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