钙/钙调蛋白依赖性激酶 IV 通过 Th17 细胞驱动的炎症性疾病中的 CCR6/CCL20 轴促进白细胞介素-17 产生细胞向靶器官的募集。
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.
机构信息
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, and Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
出版信息
Arthritis Rheumatol. 2016 Aug;68(8):1981-8. doi: 10.1002/art.39665.
OBJECTIVE
The recruitment of interleukin-17 (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 calcium/calmodulin-dependent kinase IV (CaMKIV) activation of 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.
METHODS
We induced experimental AIGN in CaMKIV-sufficient or CaMKIV-deficient mice and compared histology, Th17 cell-related chemokine expression, and numbers of IL-17-producing cells in kidneys. We also evaluated the efficacy of the CaMKIV inhibitor KN-93 in 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 peripheral blood and the severity of glomerulonephritis in patients with SLE.
RESULTS
CaMKIV-deficient mice displayed less glomerular injury after induction of AIGN. Kidney infiltration by IL-17-producing CD4+ T cells along with CCR6 and CCL20 expression were significantly decreased in CaMKIV-deficient mice. Similarly, treatment of mice with KN-93 improved clinical and pathologic outcomes. Expression and function of CCR6 in peripheral blood memory CD4+ T cells was decreased in CaMKIV-deficient mice. Expression of CCR6 correlated positively with severity of organ damage in SLE patients.
CONCLUSION
CaMKIV inhibition represents a novel therapeutic strategy for treatment of Th17 cell-mediated tissue damage in inflammatory diseases.
目的
白细胞介素-17（IL-17）产生的辅助性 T 细胞（Th17）向炎症部位的募集与包括系统性红斑狼疮（SLE）在内的炎症和自身免疫性疾病中器官损伤的发展有关。为了确定钙/钙调蛋白依赖性激酶 IV（CaMKIV）激活 Th17 细胞募集到靶组织的机制，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。
方法
我们在 CaMKIV 充足或缺乏的小鼠中诱导实验性 AIGN，并比较了组织学、Th17 细胞相关趋化因子表达和肾脏中产生 IL-17 的细胞数量。我们还评估了 CaMKIV 抑制剂 KN-93 在 AIGN 诱导的肾脏疾病中的疗效。通过流式细胞术分析 AIGN 诱导前记忆 CD4+T 细胞中 CCR6 的表达。我们研究了外周血中 CCR6 的表达与 SLE 患者肾小球肾炎严重程度之间的相关性。
结果
CaMKIV 缺乏型小鼠在诱导 AIGN 后肾小球损伤较小。CaMKIV 缺乏型小鼠肾脏中产生 IL-17 的 CD4+T 细胞浸润以及 CCR6 和 CCL20 的表达明显减少。同样，用 KN-93 治疗小鼠也改善了临床和病理结果。CaMKIV 缺乏型小鼠外周血记忆 CD4+T 细胞中 CCR6 的表达和功能降低。CCR6 的表达与 SLE 患者器官损伤的严重程度呈正相关。
结论
CaMKIV 抑制代表了治疗炎症性疾病中 Th17 细胞介导的组织损伤的一种新的治疗策略。
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