Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors
Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors
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DOI：
10.4049/jimmunol.167.11.6217
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发表时间：
2001-12-01
影响因子：
4.4
通讯作者：
Marshak-Rothstein, A
中科院分区：
文献类型：
--
作者：
Hohlbaum, AM;Gregory, MS;Marshak-Rothstein, A
Fas配体（FasL）是一种强有力的促凋亡H型跨膜蛋白，可导致Fas（+）靶群体的细胞死亡。尽管假定凋亡细胞死亡的“沉默”性质，但FasL的强制表达可诱导显著的炎症反应。为了阐明FasL和炎症的体内机制，我们使用了膜结合的无细胞形式的FasL（mFasL-囊泡制剂（VP））。我们发现，腹膜内注射FasL-微泡导致Mac 1（高）驻留腹腔巨噬细胞的快速激活和随后的死亡。在mFasL-VP注射后0.5 h内观察到Mac 1（高）腹腔巨噬细胞凋亡，并与腹腔灌洗液中巨噬细胞炎性蛋白（MIP）-2水平升高以及诱导的IL-1 β、MIP-2、MIP-1 α和MIP-1 β RNA表达相关。纯化的腹膜群体的体外培养鉴定出Mac 1（高）细胞作为响应mFasL-VP的主要细胞因子/趋化因子产生者。暴露于FasL的纯化Mac 1（高）细胞可以恢复Fas缺陷小鼠的炎症反应能力。我们的数据表明，FasL介导的炎症反应开始于凋亡前驻留组织巨噬细胞的促炎介质的产生，并提出了一个一般的机制，负责中性粒细胞炎症的情况下看到的FasL表达同种异体移植物。
Fas ligand (FasL) is a potent proapoptotic type-H transmembrane protein that can cause cell death in Fas(+) target populations. Despite the presumed "silent" nature of apoptotic cell death, forced expression of FasL can induce a dramatic inflammatory response. To elucidate the in vivo mechanism(s) linking FasL and inflammation, we used a membrane-bound cell-free form of FasL (mFasL-vesicle preparation (VP)). We found that i.p. injection of FasL-microvesicles led to the rapid activation and subsequent demise of Mac1(high) resident peritoneal macrophages. Apoptosis of Mac1(high) peritoneal macrophages was observed within 0.5 h of mFasL-VP injection and correlated with the detection of increased macrophage inflammatory protein (MIP)-2 levels in peritoneal lavage fluid as well as induced RNA expression of IL-1 beta, MIP-2, MIP-1 alpha, and MIP-1 beta. In vitro culture of purified peritoneal populations identified Mac1(high) cells as the major cytokine/chemokine producers in response to mFasL-VP. Purified Mac1(high) cells exposed to FasL could restore the ability of Fas-deficient mice to mount an inflammatory response. Our data demonstrate that the FasL-mediated inflammatory response starts with the production of proinflammatory mediators by preapoptotic resident tissue macrophages and suggest a general mechanism responsible for neutrophil inflammation seen in cases of FasL-expressing allografts.