Calcium/Calmodulin-Dependent Kinase IV Facilitates the Recruitment of Interleukin-17-Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell-Driven Inflammatory Diseases.
Calcium/Calmodulin-Dependent Kinase IV Facilitates the Recruitment of Interleukin-17-Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell-Driven Inflammatory Diseases.
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DOI：
10.1002/art.39665
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Tsokos GC
中科院分区：
文献类型：
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作者：
Koga T;Otomo K;Mizui M;Yoshida N;Umeda M;Ichinose K;Kawakami A;Tsokos GC
在炎性和自身免疫性疾病（包括系统性红斑狼疮（SLE））中，产生il -17的辅助性T细胞（Th17）向炎症部位的募集与器官损伤的发展有关。为了明确CaMK4激活th17细胞向靶组织募集的机制，我们在小鼠中进行了抗肾小球基底膜抗体诱导的肾小球肾炎（AIGN）实验，并研究了SLE患者的样本。我们在camk4充足或缺乏的小鼠中诱导实验性AIGN，并比较组织学、th17相关趋化因子的表达和肾脏中il -17产生细胞的数量。我们还评估了CaMK4拮抗剂KN-93在改变AIGN诱导的肾脏疾病中的疗效。流式细胞术分析AIGN诱导前记忆性CD4 T细胞中CCR6的表达。我们研究了SLE患者外周血CCR6表达与肾小球肾炎严重程度的相关性。camk4缺陷小鼠在AIGN诱导后表现出较少的肾小球损伤。在camk4缺陷小鼠中，产生il -17的CD4 T细胞浸润肾脏以及CCR6和CCL20的表达显著降低。同样，在暴露于AIGN之前对小鼠进行KN-93治疗可以改善临床和病理结果。camk4缺陷小鼠外周血记忆性CD4 T细胞中CCR6的表达和功能降低。CCR6的表达与SLE患者器官损害的严重程度呈正相关。我们的研究结果表明，CaMK4代表了一种治疗炎症性疾病中Th17细胞介导的组织损伤的新治疗策略。
The recruitment of IL-17-producing T helper (Th17) cells to inflammatory sites has been implicated in the development of organ damage in inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE). To define the mechanism of CaMK4 activation on Th17-cell recruitment to target tissues, we performed anti-glomerular basement membrane antibody-induced glomerulonephritis (AIGN) experiments in mice and studied samples from patients with SLE. We induced experimental AIGN in Camk4-sufficient or -deficient mice and compared histology, Th17-related chemokine expression and numbers of IL-17-producing cells in the kidneys. We also evaluated the efficacy of the CaMK4 antagonist KN-93 in alter AIGN induced kidney disease. The expression of CCR6 in memory CD4 T cells before AIGN induction was analyzed by flow cytometry. We investigated the correlation between CCR6 expression in the peripheral blood and the severity of glomerulonephritis in patients with SLE. Camk4-deficient mice displayed less glomerular injury after the induction of AIGN. Kidney infiltration by IL-17-producing CD4 T cells along with CCR6 and CCL20 expression were significantly decreased in Camk4-deficient mice. Similarly, the KN-93 treatment of mice prior to exposure to AIGN improved the clinical and pathological finings. The expression and function of CCR6 in memory CD4 T cells in the peripheral blood was decreased in the Camk4-deficient mice. The expression of CCR6 correlated positively with the severity of organ damage in SLE patients. Our results indicate that CaMK4 represents a novel therapeutic strategy for the treatment of Th17 cell-mediated tissue damage in inflammatory diseases.