Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death.
Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death.
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DOI：
10.1084/jem.20080767
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发表时间：
2008-11-24
期刊：
影响因子：
--
通讯作者：
Remold HG
中科院分区：
文献类型：
--
作者：
Chen M;Divangahi M;Gan H;Shin DS;Hong S;Lee DM;Serhan CN;Behar SM;Remold HG
强毒力结核分枝杆菌（Mtb）诱导一种适应不良的细胞溶解性死亡方式——坏死，这对病原体有利。我们报道，被强毒力Mtb菌株H37Rv和Erdmann感染的巨噬细胞发生坏死取决于主要的脂氧素A4（LXA4）产生，这是Mtb诱导的抗炎和炎症消退作用的一部分。无毒力的H37Ra感染巨噬细胞会触发高水平前列腺素E2（PGE2）的产生，它促进对线粒体内膜扰动和坏死的防护。与H37Ra感染相反，H37Rv感染的巨噬细胞中PGE2产生显著减少。PGE2通过结合PGE2受体EP2起作用，这会诱导环磷酸腺苷（cAMP）产生和蛋白激酶A激活。为了验证PGE2在控制细菌生长中的作用，我们表明在体外H37Rv感染前列腺素E合酶（PGES）缺失的巨噬细胞与野生型巨噬细胞相比，导致细菌负荷显著更高。更重要的是，在低剂量气溶胶感染强毒力Mtb 5周后，PGES缺失小鼠的Mtb肺部负荷显著更高。这些体外和体内数据表明PGE2在抑制Mtb复制中起关键作用。
Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA4 production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE2, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE2 production is significantly reduced in H37Rv-infected macrophages. PGE2 acts by engaging the PGE2 receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE2 in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)−/− macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES−/− mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE2 plays a critical role in inhibition of Mtb replication.
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作者：
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通讯作者：
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DOI：
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发表时间：
1998-12-01
影响因子：
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作者：
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