Paust Hans-Joachim, Turner Jan-Eric, Steinmetz Oliver M, Peters Anett, Heymann Felix, Hölscher Christoph, Wolf Gunter, Kurts Christian, Mittrücker Hans-Willi, Stahl Rolf A K, Panzer Ulf
Universitätsklinikum Hamburg-Eppendorf, III Medizinische Klinik, Martinistrasse 52, 20246 Hamburg, Germany.
J Am Soc Nephrol. 2009 May;20(5):969-79. doi: 10.1681/ASN.2008050556. Epub 2009 Apr 1.
T cells infiltrate the kidney in both human and experimental glomerulonephritis, and several lines of evidence indicate that T cell-mediated tissue damage plays an important role in the immunopathogenesis of renal inflammatory diseases. However, the functions of the different T cell subsets, particularly the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells), are incompletely understood in glomerulonephritis. Here, we identified renal IL-17-producing T cells in the T cell-mediated model of nephrotoxic nephritis in mice. In vitro, IL-17 enhanced the production of the proinflammatory chemokines CCL2/MCP-1, CCL3/MIP-1alpha, and CCL20/LARC, which are implicated in the recruitment of T cells and monocytes, in mouse mesangial cells. To determine the function of Th17 cells in renal inflammation, we induced nephrotoxic nephritis in IL-23 p19(-/-) mice, which have reduced numbers of Th17 cells, and in IL-17(-/-) mice, which are deficient in the effector cytokine IL-17 itself. In comparison with nephritic wild-type mice, IL-23 p19(-/-) mice demonstrated less infiltration of Th17 cells, and both IL-23 p19(-/-) and IL-17(-/-) mice developed less severe nephritis as measured by renal function, albuminuria, and frequency of glomerular crescent formation. These results demonstrate that the IL-23/IL-17 pathway significantly contributes to renal tissue injury in experimental glomerulonephritis. Targeting the IL-23/Th17 axis may be a promising therapeutic strategy for the treatment of proliferative and crescentic glomerulonephritis.
在人类和实验性肾小球肾炎中，T细胞都会浸润肾脏，多项证据表明，T细胞介导的组织损伤在肾脏炎性疾病的免疫发病机制中起重要作用。然而，在肾小球肾炎中，不同T细胞亚群的功能，尤其是最近发现的产生白细胞介素-17（IL-17）的T细胞（Th17细胞），尚未完全明确。在此，我们在小鼠肾毒性肾炎的T细胞介导模型中鉴定出了肾脏中产生IL-17的T细胞。在体外，IL-17可增强小鼠系膜细胞中促炎趋化因子CCL2/MCP-1、CCL3/MIP-1α和CCL20/LARC的产生，这些趋化因子与T细胞和单核细胞的募集有关。为了确定Th17细胞在肾脏炎症中的作用，我们在Th17细胞数量减少的IL-23 p19基因敲除小鼠以及缺乏效应细胞因子IL-17本身的IL-17基因敲除小鼠中诱导了肾毒性肾炎。与患肾炎的野生型小鼠相比，IL-23 p19基因敲除小鼠的Th17细胞浸润较少，并且通过肾功能、蛋白尿和肾小球新月体形成频率测量，IL-23 p19基因敲除小鼠和IL-17基因敲除小鼠的肾炎都较轻。这些结果表明，IL-23/IL-17途径在实验性肾小球肾炎中对肾组织损伤有显著影响。靶向IL-23/Th17轴可能是治疗增殖性和新月体性肾小球肾炎的一种有前景的治疗策略。
