NETs promote fibroblast-like synoviocytes producing IL-6 to enhance T follicular helper cell response in rheumatoid arthritis.

Objective: Although neutrophil extracellular traps (NETs) are recognized as key contributors to rheumatoid arthritis (RA) progression, their immunomodulatory effects on T follicular helper (Tfh) cell differentiation remain enigmatic. Based on the effect of NETs on RA fibroblast-like synoviocytes (RA-FLSs), our study is aimed at investigating the effect of NETs on Tfh cell differentiation in RA.

Methods: Immunofluorescence, western blotting, and flow cytometry were used to investigate whether NETs mediated the inflammatory phenotype transformation of synovium fibroblasts to produce IL-6 and promote Tfh cell differentiation through TLR9/MyD88/NF-κB pathway. The expressions of Cit H3, MPO, TLR9, and Bcl-6 in the synovial tissues of the trauma control group and the RA group were analyzed by immunohistochemistry.

Results: Our findings indicated that the plasma concentrations of IL-6 and MPO-DNA in RA patients were positively correlated with the level of IL-21 in lymphocytes and the proportion of circulating T follicular helper cells in peripheral blood. Further analysis revealed that NETs mediate the release of IL-6 from RA-FLSs through the TLR9/MyD88/NF-κB pathway, thereby inducing the differentiation of CD4 + T cells into Tfh cells and promoting the development of adaptive immunity in RA.

Conclusion: This study demonstrated that NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-κB pathway. Targeting TLR9 may be a potential target for the treatment of RA. Key Points • NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-κB pathway. • Targeting TLR9 may be a potential target for the treatment of RA.