Hamour Sally, Gan Poh-Yi, Pepper Ruth, Florez Barros Fernanda, Wang Hsu-Han, O'Sullivan Kim, Iwakura Yoichiro, Cook Terence, Pusey Charles, Holdsworth Stephen, Salama Alan
UCL Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
Centre for Inflammatory diseases, Monash University, Melbourne, Australia.
PLoS One. 2015 Aug 28;10(8):e0136238. doi: 10.1371/journal.pone.0136238. eCollection 2015.
IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases.
白细胞介素-17是一种促炎细胞因子，与肾小球肾炎的发病机制有关，白细胞介素-17缺陷型小鼠可免受肾毒性肾炎的影响。然而，白细胞介素-17的调节作用最近已显现出来。我们描述了白细胞介素-17在肾脏中的一种新的保护功能。利用野生型和白细胞介素-17缺陷型小鼠构建骨髓嵌合体，并诱导产生肾毒性肾炎。与野生型到野生型骨髓移植相比，移植野生型骨髓的白细胞介素-17缺陷型宿主在所有指标上的病情都更严重（血清尿素p<0.05；肾小球血栓形成p<0.05；肾小管损伤p<0.01），这表明在野生型小鼠中，对辐射有抗性的肾细胞产生的白细胞介素-17具有保护作用。移植野生型骨髓的白细胞介素-17缺陷型小鼠的肾脏表型也有相对改变，肾细胞因子（白细胞介素-10 p<0.01；白细胞介素-1β p<0.001；白细胞介素-23 p<0.01）和巨噬细胞表型（甘露糖受体表达p<0.05；诱导型一氧化氮合酶p<0.001）存在显著差异。最后，我们表明肾肥大细胞对辐射有抗性并产生白细胞介素-17，提示它们是疾病保护的潜在局部介质。这是肾脏中对辐射有抗性并产生白细胞介素-17以介导肾毒性肾炎保护作用的固有细胞的一种新作用。这具有临床意义，因为白细胞介素-17阻断作为一种治疗策略正在一些自身免疫性疾病中进行试验。
