PCSK9 promotes T helper 1 and T helper 17 cell differentiation by activating the nuclear factor‐κB pathway in ankylosing spondylitis

Abstract

Abstract 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 .05); its knockdown displayed the opposite function on them. Moreover, PCSK9 overexpression upregulated the p‐NF‐κB p65/NF‐κB p65 (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.

Keywords

• ankylosing spondylitis
• nuclear factor‐κB pathway
• proprotein convertase subtilisin/kexin type 9
• T helper 1 cells
• T helper 17 cells