E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection
E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection
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DOI：
10.4049/jimmunol.0900129
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发表时间：
2009-08-15
影响因子：
4.4
通讯作者：
Mancuso, Peter
中科院分区：
文献类型：
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作者：
Aronoff, David M.;Lewis, Casey;Mancuso, Peter
前列腺素 (PG) 是在感染过程中产生的有效脂质介质，其合成和信号网络为免疫调节提供了潜在的药理学靶点。 PGE(2) 通过连接四种不同的 G 蛋白偶联受体 E-前列腺素 (EP) 1-4 发挥作用。先前的体外和体内研究表明，G(αs) 偶联的 EP2 和 EP4 受体的激活可通过 cAMP 依赖性信号级联抑制对微生物病原体的炎症反应。尽管推测通过 G(αi) 偶联 EP3 受体的 PGE(2) 信号传导可能会在细菌感染（或严重炎症）的情况下抵消 EP2/EP4 免疫抑制，但这之前尚未在体内进行过测试。为了解决这个问题，我们用重要的呼吸道病原体肺炎链球菌感染野生型（EP3（+/+））和EP3（-/-）小鼠，或对小鼠进行腹腔注射。与脂多糖。出乎意料的是，我们观察到EP3(-/-)小鼠在感染或LPS后免于死亡。在受感染的 EP3(-/-) 小鼠中观察到的存活率提高与相关。增强肺部细菌清除率；肺中性粒细胞积聚减少；循环血液白细胞数量减少；以及对感染的发热反应受损。体外研究表明，EP3(-/-) 细胞的肺泡巨噬细胞吞噬和杀菌能力得到改善，这与响应免疫刺激而产生 NO 的能力增加有关。我们的研究强调了肺中宿主-微生物相互作用背景下 PGE(2) 免疫调节的复杂性。 PGE(2)-EP(3) 轴的药理学靶向代表了一个新领域，值得在预防和/或治疗传染病方面引起更大的研究兴趣。免疫学杂志，2009，183：2642-2649。
Prostaglandins (PGs) are potent lipid mediators that are produced during infections and whose synthesis and signaling networks present potential pharmacologic targets for immunomodutation. PGE(2) acts through the ligation of four distinct G protein-coupled receptors, E-prostanoid (EP) 1-4. Previous in vitro and in vivo studies demonstrated that the activation of the G(alpha s)-coupled EP2 and EP4 receptors suppresses inflammatory responses to microbial pathogens through cAMP-dependent signaling cascades. Although it is speculated that PGE(2) signaling via the G(alpha i)-coupled EP3 receptor might counteract EP2/EP4 immunosuppression in the context of bacterial infection (or severe inflammation), this has not previously been tested in vivo. To address this, we infected wild-type (EP3(+/+)) and EP3(-/-) mice with the important respiratory pathogen Streptococcus pneumoniae or injected mice i.p. with LPS. Unexpectedly, we observed that EP3(-/-) mice were protected from mortality after infection or LPS. The enhanced survival observed in the infected EP3(-/-) mice correlated with. enhanced pulmonary clearance of bacteria; reduced accumulation of lung neutrophils; lower numbers of circulating blood leukocytes; and an impaired febrile response to infection. In vitro studies revealed improved alveolar macrophage phagocytic and bactericidal capacities in EP3(-/-) cells that were associated with an increased capacity to generate NO in response to immune stimulation. Our studies underscore the complex nature of PGE(2) immunomodulation in the context of host-microbial interactions in the lung. Pharmacological targeting of the PGE(2)-EP(3) axis represents a novel area warranting greater investigative interest in the prevention and/or treatment of infectious diseases. The Journal of Immunology, 2009, 183: 2642-2649.