PCSK9 通过激活核因子-κB 通路促进强直性脊柱炎中辅助性 T 细胞 1 和辅助性 T 细胞 17 的分化。
PCSK9 promotes T helper 1 and T helper 17 cell differentiation by activating the nuclear factor-κB pathway in ankylosing spondylitis.
机构信息
Department of Rheumatology and Immunology, Huadong Hospital Affiliated with Fudan University, Shanghai, China.
Department of Traditional Chinese Medicine and Pharmacy, China Pharmaceutical University, Nanjing, China.
出版信息
Immun Inflamm Dis. 2023 May;11(5):e870. doi: 10.1002/iid3.870.
OBJECTIVE
Our previous study reveals that proprotein convertase subtilisin/kexin type 9 (PCSK9) is positively related to inflammatory markers, T helper (Th)-17 cells, and treatment response in ankylosing spondylitis (AS) patients. Subsequently, this study aimed to explore the effect of PCSK9 on Th cell differentiation and its potential molecular mechanism in AS.
METHODS
Serum PCSK9 was determined by enzyme-linked immunosorbent assay in 20 AS patients and 20 healthy controls (HCs). Then naïve CD4 T cells were isolated from AS patients and infected with PCSK9 overexpression or knockdown adenovirus followed by polarization assay. Afterward, PMA (an NF-κB activator) was administrated.
RESULTS
PCSK9 was increased in AS patients compared to HCs (p < .001), and it was positively related to Th1 cells (p = .050) and Th17 cells (p = .039) in AS patients. PCSK9 overexpression increased the CD4 IFN-γ cells (p < .05), CD4 IL-17A cells (p < .01), IFN-γ (p < .01), and IL-17A (p < .01), while it exhibited no effect on CD4 IL-4 cells or IL-4 (both p > .05); its knockdown displayed the opposite function on them. Moreover, PCSK9 overexpression upregulated the p-NF-κB p65/NF-κB p65 (p < .01), while it had no effect on p-ERK/ERK or p-JNK/JNK (both p > .05); its knockdown decreased p-NF-κB p65/NF-κB p65 (p < .01) and p-JNK/JNK (p < .05). Then, PMA upregulates p-NF-κB p65/NF-κB p65 (p < .001) and increased CD4 IFN-γ cells, CD4 IL-17A cells, IFN-γ, and IL-17A (all p < .01), also it alleviated the effect of PCSK9 knockdown on NF-κB inhibition and Th cell differentiation (all p < .01).
CONCLUSION
PCSK9 enhances Th1 and Th17 cell differentiation in an NF-κB-dependent manner in AS, while further validation is necessary.
目的
我们之前的研究表明，前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）与炎症标志物、辅助性 T 细胞（Th）-17 细胞和强直性脊柱炎（AS）患者的治疗反应呈正相关。随后，本研究旨在探讨 PCSK9 对 Th 细胞分化的影响及其在 AS 中的潜在分子机制。
方法
采用酶联免疫吸附试验（ELISA）检测 20 例 AS 患者和 20 例健康对照者（HCs）血清 PCSK9 水平。然后，从 AS 患者中分离出幼稚 CD4 T 细胞，并用过表达或敲低 PCSK9 的腺病毒感染，再进行极化实验。之后，用 PMA（NF-κB 激活剂）进行处理。
结果
与 HCs 相比，AS 患者的 PCSK9 升高（p<0.001），且与 AS 患者的 Th1 细胞（p=0.050）和 Th17 细胞（p=0.039）呈正相关。PCSK9 过表达增加 CD4 IFN-γ 细胞（p<0.05）、CD4 IL-17A 细胞（p<0.01）、IFN-γ（p<0.01）和 IL-17A（p<0.01），而对 CD4 IL-4 细胞或 IL-4 无影响（均 p>0.05）；其敲低则对它们产生相反的作用。此外，PCSK9 过表达上调 p-NF-κB p65/NF-κB p65（p<0.01），而对 p-ERK/ERK 或 p-JNK/JNK 无影响（均 p>0.05）；其敲低则降低 p-NF-κB p65/NF-κB p65（p<0.01）和 p-JNK/JNK（p<0.05）。然后，PMA 上调 p-NF-κB p65/NF-κB p65（p<0.001），并增加 CD4 IFN-γ 细胞、CD4 IL-17A 细胞、IFN-γ 和 IL-17A（均 p<0.01），同时减轻 PCSK9 敲低对 NF-κB 抑制和 Th 细胞分化的影响（均 p<0.01）。
结论
PCSK9 以 NF-κB 依赖的方式增强 AS 中的 Th1 和 Th17 细胞分化，但其确切机制仍需进一步验证。
Zotero 插件