Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
Arthritis Res Ther. 2019 Aug 20;21(1):191. doi: 10.1186/s13075-019-1973-0.
Lysophosphatidic acid (LPA), generated by autotaxin (ATX), is a bioactive lipid mediator that binds to the receptors (LPA), and serves as an important mediator in inflammation. Previous studies have demonstrated that LPA-LPA 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.
ATX and LPA receptor expressions were analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Effects of LPA inhibition on CAWS-induced vasculitis were evaluated in LPA-deficient mice or using an LPA 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.
ATX and LPA were highly expressed in the inflamed region of CAWS-induced vasculitis. Severity of the vasculitis in LPA-deficient mice was suppressed. The LPA 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 LPA-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 LPA expression levels were higher in the affected skin region of vasculitis patients than in healthy controls.
These results suggest that LPA-LPA signaling contributes to the development of vasculitis via chemoattractant production from endothelial cells followed by neutrophil recruitment. Thus, LPA has potential as a novel target for vasculitis therapies.
溶血磷脂酸（LPA）由自分泌酶（ATX）生成，是一种生物活性脂质介质，与受体（LPA）结合，作为炎症的重要介质。先前的研究表明，LPA-LPA 级联反应有助于关节炎和皮肤硬化。在这项研究中，我们研究了 LPA 信号在小鼠白色念珠菌水溶性部分（CAWS）诱导的血管炎中的作用。
通过免疫组织化学和定量逆转录聚合酶链反应分析 ATX 和 LPA 受体的表达。在 LPA 缺陷小鼠或使用 LPA 拮抗剂 LA-01 评估 LPA 抑制对 CAWS 诱导的血管炎的影响。使用趋化性室评估 LPA 的迁移活性。在血管炎小鼠的主动脉壁中计数转移的荧光标记中性粒细胞的数量。通过酶联免疫吸附试验测定 CXCL1 和 IL-8 浓度。
ATX 和 LPA 在 CAWS 诱导的血管炎的炎症区域高度表达。LPA 缺陷小鼠的血管炎严重程度降低。LPA 拮抗剂 LA-01 也改善了 CAWS 诱导的血管炎。LPA 诱导中性粒细胞迁移，LA-01 在体外抑制该迁移。从 LPA 缺陷小鼠转移的中性粒细胞浸润到冠状动脉被抑制。LA-01 也抑制了野生型中性粒细胞的浸润。LPA 增强人内皮细胞中 CXCL1 和 IL-8 的表达，但被 LA-01 抑制。与健康对照组相比，血管炎患者受影响皮肤区域的 ATX 和 LPA 表达水平更高。
这些结果表明，LPA-LPA 信号通过内皮细胞产生趋化因子并随后招募中性粒细胞参与血管炎的发展。因此，LPA 可能成为血管炎治疗的新靶点。
