Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
J Cell Mol Med. 2020 Mar;24(5):3064-3078. doi: 10.1111/jcmm.14967. Epub 2020 Feb 5.
Th22 cells are a novel subset of CD4 T cells that primarily mediate biological effects through IL-22, with both Th22 cells and IL-22 being closely associated with multiple autoimmune and chronic inflammatory diseases. In this study, we investigated whether and how Th22 cells affect atherosclerosis. ApoE mice and age-matched C57BL/6J mice were fed a Western diet for 0, 4, 8 or 12 weeks. The results of dynamic analyses showed that Th22 cells, which secrete the majority of IL-22 among the known CD4 cells, play a major role in atherosclerosis. ApoE mice fed a Western diet for 12 weeks and administered recombinant mouse IL-22 (rIL-22) developed substantially larger plaques in both the aorta and aortic root and higher levels of CD3 T cells, CD68 macrophages, collagen, IL-6, Th17 cells, dendritic cells (DCs) and pSTAT3 but lower smooth muscle cell (SMC) α-actin expression than the control mice. Treatment with a neutralizing anti-IL-22 monoclonal antibody (IL-22 mAb) reversed the above effects. Bone marrow-derived DCs exhibited increased differentiation into mature DCs following rIL-22 and ox-LDL stimulation. IL-17 and pSTAT3 were up-regulated after stimulation with IL-22 and ox-LDL in cells cocultured with CD4 T cells and mature DC supernatant, but this up-regulation was significantly inhibited by IL-6mAb or the cell-permeable STAT3 inhibitor S31-201. Thus, Th22 cell-derived IL-22 aggravates atherosclerosis development through a mechanism that is associated with IL-6/STAT3 activation, DC-induced Th17 cell proliferation and IL-22-stimulated SMC dedifferentiation into a synthetic phenotype.
Th22 细胞是一种新型的 CD4 T 细胞亚群，主要通过 IL-22 发挥生物学效应，Th22 细胞和 IL-22 均与多种自身免疫和慢性炎症性疾病密切相关。在本研究中，我们研究了 Th22 细胞是否以及如何影响动脉粥样硬化。apoE 小鼠和年龄匹配的 C57BL/6J 小鼠分别用西方饮食喂养 0、4、8 或 12 周。动态分析结果显示，Th22 细胞（已知 CD4 细胞中分泌大部分 IL-22 的细胞亚群）在动脉粥样硬化中起主要作用。用西方饮食喂养 12 周并给予重组鼠 IL-22（rIL-22）的 apoE 小鼠，在主动脉和主动脉根部形成的斑块明显增大，CD3 T 细胞、CD68 巨噬细胞、胶原、IL-6、Th17 细胞、树突状细胞（DC）和 pSTAT3 水平升高，而平滑肌细胞（SMC）α-肌动蛋白表达降低，与对照组相比。用中和抗 IL-22 单克隆抗体（IL-22 mAb）治疗可逆转上述作用。rIL-22 和 ox-LDL 刺激后，骨髓来源的 DC 向成熟 DC 的分化增加。与 CD4 T 细胞和成熟 DC 上清液共培养的细胞中，经 IL-22 和 ox-LDL 刺激后，IL-17 和 pSTAT3 上调，但用 IL-6mAb 或细胞通透型 STAT3 抑制剂 S31-201 可显著抑制这种上调。因此，Th22 细胞来源的 IL-22 通过与 IL-6/STAT3 激活、DC 诱导的 Th17 细胞增殖和 IL-22 刺激 SMC 向合成表型分化相关的机制加重动脉粥样硬化的发展。
