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

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 naive CD4(+) T cells were isolated from AS patients and infected with PCSK9 overexpression or knockdown adenovirus followed by polarization assay. Afterward, PMA (an NF-?B 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-?(+) cells (p < .05), CD4(+)IL-17A(+) cells (p < .01), IFN-? (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-?B p65/NF-?B p65 (p < .01), while it had no effect on p-ERK/ERK or p-JNK/JNK (both p > .05); its knockdown decreased p-NF-?B p65/NF-?B p65 (p < .01) and p-JNK/JNK (p < .05). Then, PMA upregulates p-NF-?B p65/NF-?B p65 (p < .001) and increased CD4(+)IFN-?(+) cells, CD4(+)IL-17A(+) cells, IFN-?, and IL-17A (all p < .01), also it alleviated the effect of PCSK9 knockdown on NF-?B inhibition and Th cell differentiation (all p < .01).Conclusion: PCSK9 enhances Th1 and Th17 cell differentiation in an NF-?B-dependent manner in AS, while further validation is necessary.