Regenerative Medicine Institute, National Centre for Biomedical Engineering Science and School of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.
Kidney Int. 2012 Feb;81(4):379-90. doi: 10.1038/ki.2011.348. Epub 2011 Oct 5.
Interleukin 17A-secreting T-helper 17 (Th17) cells are pathogenic in inflammatory kidney diseases, but their intrarenal regulation is poorly understood. In order to better define Th17 cell dynamics during interstitial inflammation, we utilized the mouse unilateral ureteral obstruction model to analyze inflammatory cell subtypes by multicolor flow cytometry and cell sorting and by effects on in vitro-generated Th17 cells. Interleukin 17A expression localized to CCR6(+)CCR4(+/-)CD4(+) T-cells and progressively increased in obstructed kidneys. The number of CCR6(+)CD4(+) T-cells increased over 10-fold by 72 h, were enriched for interleukin 17A production, and were highly proliferative based on in vivo bromodeoxyuridine incorporation. Secreted products of leukocytes isolated from obstructed kidneys enhanced the interleukin 17A production of in vitro-generated Th17 cells. This Th17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking the interleulin-1 receptor and in mice treated with a recombinant interleukin-1 receptor antagonist, each of which exhibited reduced intrarenal Th17 activity compared with control mice. Thus, the inflamed kidney accumulates CCR6(+) Th17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intrarenal Th17 activation in acute kidney injury.
白细胞介素 17A 分泌 T 辅助细胞 17（Th17）在炎症性肾病中具有致病性，但它们在肾脏内的调节机制尚不清楚。为了更好地定义 Th17 细胞在间质炎症期间的动态变化，我们利用单侧输尿管梗阻模型，通过多色流式细胞术和细胞分选分析炎症细胞亚型，并通过对体外生成的 Th17 细胞的影响来分析炎症细胞亚型。白细胞介素 17A 的表达定位于 CCR6（+）CCR4（+/-）CD4（+）T 细胞，并且在梗阻肾脏中逐渐增加。CCR6（+）CD4（+）T 细胞的数量在 72 小时内增加了 10 倍以上，富含白细胞介素 17A 的产生，并根据体内溴脱氧尿苷掺入而具有高度增殖性。从梗阻肾脏中分离的白细胞分泌产物增强了体外生成的 Th17 细胞的白细胞介素 17A 产生。这种增强 Th17 细胞的活性被鉴定为肾脏树突状细胞和单核细胞产生的白细胞介素 1。这些发现的体内有效性在缺乏白细胞介素 1 受体的小鼠和用重组白细胞介素 1 受体拮抗剂治疗的小鼠中得到了证实，与对照组小鼠相比，每种小鼠的肾脏内 Th17 活性均降低。因此，发炎的肾脏会积累 CCR6（+）Th17 细胞，这些细胞会发生激活和增殖。驻留树突状细胞和浸润单核细胞产生的白细胞介素 1 家族细胞因子增强了急性肾损伤中肾脏内 Th17 的激活。
