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.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table>

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

期刊论文
发表日期：

2025年7月19日

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Zijia Li,
Yali Liu,
Yan Zhang,
Zhichun Zhang,
Shangwen Lei,
Haili Shen

摘要

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.