Department of Pediatrics, Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University, Kaohsiung, Taiwan.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Clin Immunol. 2024 Mar 7;44(3):77. doi: 10.1007/s10875-024-01673-1.
To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA).
In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected.
The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra littermates, and absent IL-17RA upregulation at aortic roots.
IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.
评估白细胞介素（IL）-17A/IL-17 受体 A（IL-17RA）在川崎病（KD）相关冠状动脉炎（CA）中的作用。
在人体研究中，同时检查急性 KD 患者的血浆 IL-17A 水平和冠状动脉。研究了人冠状动脉内皮细胞对血浆刺激的体外反应，并在有无 IL-17RA 中和的情况下进行了研究。还使用野生型 Balb/c 和 Il17ra 缺陷型小鼠检查了乳酸乳球菌细胞壁提取物（LCWE）诱导的 CA 小鼠模型。
KD 患者在静脉免疫球蛋白治疗前的血浆 IL-17A 水平明显升高，尤其是在伴有冠状动脉病变的患者中。前 IVIG IL-17A 水平与冠状动脉直径的最大 z 评分以及血浆诱导的内皮细胞趋化因子（C-X-C 基序）配体-1、IL-8 和 IL-17RA 的 mRNA 水平呈正相关。IL-17RA 阻断显著降低了上述三种基因和诱导型一氧化氮合酶以及中性粒细胞迁移的这种内皮上调。在 IVIG 前 KD 患者的外周血单核细胞、LCWE 刺激的小鼠的主动脉环和脾脏中，IL-17RA 表达增强。LCWE 诱导的 CA 由双阳性 Ly6G-和 IL-17A 染色浸润组成。与 Il17ra 同窝仔相比，Il17ra 缺陷型小鼠的 CA 严重程度降低，中性粒细胞数量减少，早期诱导型一氧化氮合酶和趋化因子（C-X-C 基序）配体-1 mRNA 表达降低，主动脉根部无 IL-17RA 上调。
IL-17A/IL-17RA 轴可能在介导主动脉中性粒细胞趋化作用中起作用，从而有助于人类和小鼠 CA 的严重程度。这些发现可能有助于开发改善 KD 相关 CA 的新治疗策略。
