The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria.
The adhesion GPCR BAI1 mediates macrophage ROS production and microbicidal activity against Gram-negative bacteria.
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DOI：
10.1126/scisignal.aac6250
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发表时间：
2016-02-02
影响因子：
7.3
通讯作者：
Casanova JE
中科院分区：
文献类型：
--
作者：
Billings EA;Lee CS;Owen KA;D'Souza RS;Ravichandran KS;Casanova JE
微生物的检测和先天免疫应答的启动通过模式识别受体（PRR）发生，其对于炎性细胞因子的产生和细胞杀微生物机制的激活是关键的。特别地，通过NADPH氧化酶复合物产生活性氧（ROS）是巨噬细胞杀菌机制的关键组分。我们以前的特点是脑特异性血管生成抑制因子1（BAI1），G蛋白（异源三聚体鸟嘌呤核苷酸结合蛋白）偶联受体（GPCR）的粘附家族的成员，作为一个PRR介导的选择性吞噬巨噬细胞的革兰氏阴性菌的摄取。我们发现，BAI 1通过激活Rho家族鸟苷三磷酸酶（GTdR）Rac 1，从而刺激NADPH氧化酶活性，促进吞噬体ROS的产生。原代BAI 1缺陷型巨噬细胞对几种革兰氏阴性菌的反应表现出减弱的Rac GT3活性和减少的ROS产生，导致杀菌活性受损。此外，在腹膜感染模型中，由于细菌清除受损，BAI 1缺陷小鼠对细菌攻击的死亡易感性增加。总之，这些研究结果表明，BAI1介导的清除革兰氏阴性菌刺激吞噬和NADPH氧化酶的激活，从而耦合细菌检测到细胞的杀微生物机制。
The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages. We showed that BAI1 promoted phagosomal ROS production through activation of the Rho family guanosine triphosphatase (GTPase) Rac1, thereby stimulating NADPH oxidase activity. Primary BAI1-deficient macrophages exhibited attenuated Rac GTPase activity and reduced ROS production in response to several Gram-negative bacteria, resulting in impaired microbicidal activity. Furthermore, in a peritoneal infection model, BAI1-deficient mice exhibited increased susceptibility to death by bacterial challenge because of impaired bacterial clearance. Together, these findings suggest that BAI1 mediates the clearance of Gram-negative bacteria by stimulating both phagocytosis and NADPH oxidase activation, thereby coupling bacterial detection to the cellular microbicidal machinery.