Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Pediatric Research Institute, Children's Hospital of Chongqing Medical University, Chongqing, China.
Cell Death Differ. 2022 Oct;29(10):1901-1912. doi: 10.1038/s41418-022-00973-6. Epub 2022 Apr 21.
T helper 2 (Th2) cytokine production by invariant natural killer T (iNKT) cells is involved in the development of asthma, but the regulation of Th2 cytokines in iNKT cells remains unknown. Although it is known that progranulin (PGRN) induces the production of Th2 cytokines in iNKT cells in vivo, the underlying mechanism is not clear. This study aims to investigate the role of PGRN in iNKT cells. The effects of PGRN on the differentiation of iNKT cells was detected by flow cytometry. Then stimulation of iNKT cells and airway resistance were carried out to evaluate the function of PGRN on iNKT cells. Furthermore, the mechanisms of PGRN in regulating iNKT cells was investigated by RT-PCR, WB, confocal and luciferase reporter assays. The absolute number of iNKT cells decreased in PGRN KO mice despite an increase in the percentage of iNKT cells. Furthermore, analyzing the subsets of iNKT cells, we found that NKT2 cells and their IL-4 production were reduced. Mechanistically, the decrease in NKT2 cells in the PGRN KO mice was caused by increased expression of enhancer of zeste homolog 2 (EZH2), that in turn caused increased degradation and altered nuclear localization of PLZF. Interestingly, PGRN signaling decreased expression of EZH2 and treatment of the PGRN KO mice with the EZH2 specific inhibitor GSK343 rescued the defect in NKT2 differentiation, IL-4 generation, and PLZF expression. Altogether, We have revealed a new pathway (PGRN-EZH2-PLZF), which regulates the Th2 responses of iNKT cells and provides a potentially new target for asthma treatment.
固有自然杀伤 T(iNKT)细胞产生的辅助性 T 细胞 2(Th2)细胞因子参与哮喘的发生，但 iNKT 细胞中 Th2 细胞因子的调节尚不清楚。虽然已知颗粒蛋白前体(PGRN)在体内诱导 iNKT 细胞产生 Th2 细胞因子，但潜在机制尚不清楚。本研究旨在探讨 PGRN 在 iNKT 细胞中的作用。通过流式细胞术检测 PGRN 对 iNKT 细胞分化的影响。然后刺激 iNKT 细胞和气道阻力，评估 PGRN 对 iNKT 细胞的功能。此外，通过 RT-PCR、WB、共聚焦和荧光素酶报告基因检测研究了 PGRN 调节 iNKT 细胞的机制。尽管 iNKT 细胞的百分比增加，但 PGRN KO 小鼠中的 iNKT 细胞绝对数减少。此外，分析 iNKT 细胞亚群，我们发现 NKT2 细胞及其 IL-4 产生减少。从机制上讲，PGRN KO 小鼠中 NKT2 细胞的减少是由增强子结合蛋白 2(EZH2)表达增加引起的，这反过来又导致 PLZF 的降解和核定位改变。有趣的是，PGRN 信号降低了 EZH2 的表达，用 EZH2 特异性抑制剂 GSK343 处理 PGRN KO 小鼠可挽救 NKT2 分化、IL-4 产生和 PLZF 表达的缺陷。总之，我们揭示了一个新的通路(PGRN-EZH2-PLZF)，它调节 iNKT 细胞的 Th2 反应，并为哮喘治疗提供了一个潜在的新靶点。
