TH17-cell migration from the intestine to the kidney is S1P receptor 1-dependent and drives immune-mediated renal disease. TH17

The relationship between microbiota-induced TH17 cells in the intestine and pathogenic TH17responses in autoimmune diseases is still unclear. Here, we report high frequencies of CD4+TH17 cells in the kidneys of patients with ANCA-associated crescentic glomerulonephritis andin a mouse model of crescentic glomerulonephritis. By photoconverting intestinal cells inKaede-transgenic mice, we provide direct evidence for the migration of TH17 cells from theintestine into the inflamed kidney via the CCR6/CCL20 axis. Accordingly, the absence ofintestinal TH 17 cells in germ-free mice and their depletion in antibiotics-treated mice reducedrenal T H17 response and the consecutive tissue injury in glomerulonephritis. In contrast,expansion of intestinal T H17 cells in Citrobacter rodentium infected mice exerted the oppositeeffect. These findings reveal that pathogenic TH17 cells in crescentic glomerulonephritisoriginate from the intestine, migrate into the kidney and drive tissue injury. This might havesignificant implications for the treatment of TH17-driven autoimmune disorders.

肠道内菌群诱导的TH17细胞与自身免疫病中致病性TH17应答之间的关联仍未明确。本研究报道，抗中性粒细胞胞浆抗体相关性新月体性肾小球肾炎(ANCA-associated crescentic glomerulonephritis)患者及该疾病小鼠模型的肾脏组织中，CD4+TH17细胞的检出频率显著升高。通过对Kaede转基因小鼠(Kaede-transgenic mice)的肠道细胞进行光转换操作，本研究为TH17细胞经CCR6/CCL20轴从肠道迁移至炎症性肾脏提供了直接实验证据。相应地，无菌小鼠肠道内TH17细胞的缺失，以及抗生素处理小鼠体内肠道TH17细胞的耗竭，均可减轻肾小球肾炎模型中的肾脏TH17应答及继发的组织损伤。与之相反，鼠柠檬酸杆菌(Citrobacter rodentium)感染小鼠体内肠道TH17细胞的扩增则呈现出相反的效应。上述研究结果表明，新月体性肾小球肾炎中的致病性TH17细胞起源于肠道，迁移至肾脏并驱动组织损伤。这一发现对TH17细胞介导的自身免疫失调的临床治疗具有重要的指导意义。