Abrogation of lysophosphatidic acid receptor 1 ameliorates murine vasculitis
Abrogation of lysophosphatidic acid receptor 1 ameliorates murine vasculitis
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DOI：
10.1186/s13075-019-1973-0
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发表时间：
2019-08-20
影响因子：
4.9
通讯作者：
Nanki, Toshihiro
中科院分区：
文献类型：
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作者：
Miyabe, Chie;Miyabe, Yoshishige;Nanki, Toshihiro
背景：溶血磷脂酸(LPA)由自体趋化蛋白(ATX)产生，是一种与受体(LPA1-6)结合的生物活性脂质介质，是炎症反应中的重要介质。以前的研究已经证明，LPA-LPA1级联反应会导致关节炎和皮肤硬化。本研究探讨LPA信号在白念珠菌水溶性部分(CAWS)诱导的小鼠血管炎症中的作用。方法：采用免疫组织化学和定量逆转录聚合酶链式反应(QRT-PCR)检测ATX和LPA受体的表达。在LPA1缺陷小鼠或使用LPA1拮抗剂LA-01评估LPA1抑制对Caws诱导的血管炎的影响。趋化性小室用于评估迁移活性。将迁移到血管炎小鼠体内的荧光标记的中性粒细胞在主动脉壁计数。结果：ATX和LPA1在Caws诱导的小血管炎症部位均有高表达。抑制LPA1基因缺陷小鼠血管炎的严重程度。LPA1拮抗剂LA-01也能改善Caws诱导的小血管炎。LPA在体外可诱导中性粒细胞迁移，而LA-01对其有抑制作用。LPA1缺陷小鼠转移的中性粒细胞对冠状动脉的渗透受到抑制。LA-01还能抑制野生型中性粒细胞的渗入。LPA可促进人内皮细胞CXCL1和IL-8的表达，而LA-01则抑制其表达。ATX和LPA1在血管炎患者皮肤区的表达水平均高于正常对照组。结论：LPA-LPA1信号通路通过内皮细胞产生趋化物质和中性粒细胞募集参与了血管炎的发生发展。因此，LPA1有可能成为治疗血管炎的新靶点。
Background: Lysophosphatidic acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the receptors (LPA1-6), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA1 cascade contributes to arthritis and skin sclerosis. In this study, we examined the role of LPA signals in murine Candida albicans water-soluble fraction (CAWS)-induced vasculitis.Methods: ATX and LPA receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA1 inhibition on CAWS-induced vasculitis were evaluated in LPA1deficient mice or using an LPA1 antagonist, LA-01. Migration activity was assessed using a chemotaxis chamber. The number of migrated fluorescently labeled neutrophils, which were transferred into the vasculitis mice, was counted in the aortic wall. CXCL1 and IL-8 concentrations were determined by enzyme-linked immunosorbent assay.Results: ATX and LPA1 were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA1-deficient mice was suppressed. The LPA1 antagonist, LA-01, also ameliorated the CAWS-induced vasculitis. LPA induced neutrophil migration, which was inhibited by LA-01 in vitro. Infiltration of transferred neutrophils from LPA1-deficient mice into the coronary arteries was suppressed. LA-01 also inhibited the infiltration of wild-type neutrophils. Expression of CXCL1 and IL-8 in human endothelial cells was enhanced by LPA, but was inhibited by LA-01. ATX and LPA1 expression levels were higher in the affected skin region of vasculitis patients than in healthy controls.Conclusions: These results suggest that LPA-LPA1 signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA1 has potential as a novel target for vasculitis therapies.