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Loss of IL-27Rα Results in Enhanced Tubulointerstitial Fibrosis Associated with Elevated Th17 Responses
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-10 , DOI: 10.4049/jimmunol.1901463
Gaia M Coppock 1, 2 , Lillian R Aronson 1, 3 , Jihwan Park 2 , Chengxiang Qiu 2 , Jeongho Park 1 , Jonathan H DeLong 1 , Enrico Radaelli 1 , Katalin Suszták 2 , Christopher A Hunter 4
Affiliation  

Key Points Th17 cells are associated with renal dysfunction and IL-27 suppresses these cells. IL-27R limits renal fibrosis after UUO. Visual Abstract Clinical and experimental studies have established that immune cells such as alternatively activated (M2) macrophages and Th17 cells play a role in the progression of chronic kidney disease, but the endogenous pathways that limit these processes are not well understood. The cytokine IL-27 has been shown to limit immune-mediated pathology in other systems by effects on these cell types, but this has not been thoroughly investigated in the kidney. Unilateral ureteral obstruction was performed on wild-type and IL-27Rα−/− mice. After 2 wk, kidneys were extracted, and the degree of injury was measured by hydroxyproline assay and quantification of neutrophil gelatinase–associated lipocalin mRNA. Immune cell infiltrate was evaluated by immunohistochemistry and flow cytometry. An anti–IL-17A mAb was subsequently administered to IL-27Rα−/− mice every 2 d from day of surgery with evaluation as described after 2 wk. After unilateral ureteral obstruction, IL-27 deficiency resulted in increased tissue injury and collagen deposition associated with higher levels of chemokine mRNA and increased numbers of M2 macrophages. Loss of the IL-27Rα led to increased infiltration of activated CD4+ T cells that coproduced IL-17A and TNF-α, and blockade of IL-17A partially ameliorated kidney injury. Patients with chronic kidney disease had elevated serum levels of IL-27 and IL-17A, whereas expression of transcripts for the IL-27RA and the IL-17RA in the tubular epithelial cells of patients with renal fibrosis correlated with disease severity. These data suggest that endogenous IL-27 acts at several points in the inflammatory cascade to limit the magnitude of immune-mediated damage to the kidney.

中文翻译:

IL-27Rα 的缺失导致与 Th17 反应升高相关的肾小管间质纤维化增强

关键点 Th17 细胞与肾功能障碍有关,而 IL-27 会抑制这些细胞。IL-27R 限制 UUO 后的肾纤维化。视觉摘要 临床和实验研究已经确定免疫细胞,如交替激活 (M2) 巨噬细胞和 Th17 细胞在慢性肾病的进展中发挥作用,但限制这些过程的内源性途径尚不清楚。细胞因子 IL-27 已被证明通过对这些细胞类型的影响来限制其他系统中免疫介导的病理学,但这尚未在肾脏中进行彻底研究。对野生型和 IL-27Rα-/- 小鼠进行单侧输尿管阻塞。2 周后,提取肾脏,通过羟脯氨酸测定和中性粒细胞明胶酶相关脂质运载蛋白 mRNA 的定量测量损伤程度。通过免疫组织化学和流式细胞术评估免疫细胞浸润。随后从手术当天起每 2 天向 IL-27Rα-/- 小鼠施用抗 IL-17A mAb,并在 2 周后进行评估。单侧输尿管梗阻后,IL-27 缺乏导致组织损伤和胶原沉积增加,与更高水平的趋化因子 mRNA 和 M2 巨噬细胞数量增加相关。IL-27Rα 的缺失导致激活的 CD4+ T 细胞浸润增加,这些细胞共同产生 IL-17A 和 TNF-α,阻断 IL-17A 可部分改善肾损伤。慢性肾病患者血清 IL-27 和 IL-17A 水平升高,而肾纤维化患者肾小管上皮细胞中 IL-27RA 和 IL-17RA 转录物的表达与疾病严重程度相关。
更新日期:2020-06-10
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