Serum amyloid A mediates human neutrophil production of reactive oxygen species through a receptor independent of formyl peptide receptor like-1
Serum amyloid A mediates human neutrophil production of reactive oxygen species through a receptor independent of formyl peptide receptor like-1
复制标题
血清淀粉样蛋白 A 通过独立于甲酰肽受体-1 的受体介导人中性粒细胞产生活性氧
DOI：
10.1189/jlb.0607-408
复制
发表时间：
2008-02-01
影响因子：
5.5
通讯作者：
Dahlgren, Claes
中科院分区：
文献类型：
--
作者：
Bjoerkman, Lena;Karlsson, Jennie;Dahlgren, Claes
血清淀粉样蛋白A(SAA)是类风湿关节炎(RA)的急性期反应物之一，是一组在微生物感染和炎症条件下浓度急剧升高的血浆蛋白，其水平与疾病活动性密切相关。RA是一种炎症性疾病，中性粒细胞在其中起重要作用，SAA被认为通过中性粒细胞趋化因子和促炎细胞因子的诱导剂参与炎症反应。据报道，SAA的生物学效应主要是通过甲酰肽受体样1(FPRL1)介导的，FPRL1是一种属于甲酰肽受体家族的G蛋白偶联受体(GPCR)。在这里，我们证实了SAA与FPRL1的亲和力，结果表明，稳定表达FPRL1的HL-60细胞可被SAA激活，而FPRL1特异性拮抗剂WRWWWW(WRW4)可抑制这一反应。我们还发现SAA激活了中性粒细胞NADPH-氧化酶，并且在由来自革兰氏阴性细菌的肿瘤坏死因子-α和脂多糖等启动剂动员的存储细胞器中存在一个受体储备池。百日咳毒素可抑制其诱导活性，表明GPCR参与其中。然而，基于FPRL1的特异性脱敏和FPRL1拮抗剂WRW4的使用，我们发现SAA介导的中性粒细胞效应不依赖于FPRL1。基于这些发现，我们得出结论，中性粒细胞中的SAA信号是通过GPCR介导的，不同于FPRL1。未来对SAA受体的鉴定和鉴定可能会导致开发治疗RA的新的治疗靶点。
Serum amyloid A (SAA) is one of the acute-phase reactants, a group of plasma proteins that increases immensely in concentration during microbial infections and inflammatory conditions, and a close relationship between SAA levels and disease activity in rheumatoid arthritis (RA) has been observed. RA is an inflammatory disease, where neutrophils play important roles, and SAA is thought to participate in the inflammatory reaction by being a neutrophil chemoattractant and inducer of proinflammatory cytokines. The biological effects of SAA are reportedly mediated mainly through formyl peptide receptor like-1 (FPRL1), a G protein-coupled receptor (GPCR) belonging to the formyl peptide receptor family. Here, we confirmed the affinity of SAA for FPRL1 by showing that stably transfected HL-60 cells expressing FPRL1 were activated by SAA and that the response was inhibited by the use of the FPRL1-specific antagonist WRWWWW (WRW4). We also show that SAA activates the neutrophil NADPH-oxidase and that a reserve pool of receptors is present in storage organelles mobilized by priming agents such as TNF-alpha and LPS from Gram-negative bacteria. The induced activity was inhibited by pertussis toxin, indicating the involvement of a GPCR. However, based on FPRL1-specific desensitization and use of FPRL1 antagonist WRW4, we found the SAA-mediated effects in neutrophils to be independent of FPRL1. Based on these findings, we conclude that SAA signaling in neutrophils is mediated through a GPCR, distinct from FPRL1. Future identification and characterization of the SAA receptor could lead to development of novel, therapeutic targets for treatment of RA.