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Background <p>Our previous research has shown that lipopolysaccharide (LPS) derived from Gram-negative bacteria in the intestine promoted rheumatoid arthritis (RA) after entering peripheral blood, but the specific molecular mechanism was unclear.</p> Method <p>This study used transcriptome and proteomic sequencing, western blotting, co-immunoprecipitation (Co-IP), cell co-culture, and other related methods to investigate whether LPS entering peripheral blood activated the Wnt7b secretion in macrophages, and used the Wnt7b as a messenger molecule to promote the communication between macrophage-fibroblast-like synoviocyte (FLSs), ultimately leading to the onset of RA.</p> Result <p>The results showed that LPS significantly promoted the pathology of collagen induced arthritis (CIA) mice. Transcriptome and proteomic sequencing, as well as experimental validation, confirmed that the target of LPS may be the Wnt7b. Knocking down the Wnt7b in CIA mice could effectively alleviate the LPS induced pathology. Furthermore, in the M<sub>0</sub> macrophage-FLS co-culture system, overexpression of Wnt7b in M<sub>0</sub> macrophages promoted the expression of RA pathological factors in FLSs and activated the <i>WNT/CTNNB1</i> signaling pathway of FLSs. However, knocking down the <i>Wnt7b</i> in M<sub>1</sub> macrophages resulted in the opposite effects. Interestingly, in the M<sub>0</sub> macrophage-FLS co-culture system, overexpression of Wnt7b in M<sub>0</sub> macrophages could enhance the expression of frizzled class receptor 8 (FZD8) on FLSs, activating the Wnt/β-catenin signaling pathway of FLSs. However, knocking down the <i>FZD8</i> in FLSs after overexpression of Wnt7b could interfere with the effects of overexpression of Wnt7b. In addition, adding LPS to M<sub>0</sub> macrophages promoted the FZD8 expression of co-cultured FLSs and activated the Wnt/β-catenin signaling pathway. Knocking down FZD8 in FLSs after adding LPS to M0 macrophages could interfere with the effects of LPS.</p> Conclusion <p>This study suggested that circulating LPS stimulated macrophages to secrete Wnt7b, which acted as a messenger molecule and bound to the FZD8 receptor on the FLSs cell membrane in the synovial microenvironment, promoting the activation of the Wnt/β-catenin signaling pathway in FLSs and leading to RA.</p>

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Lipopolysaccharide promotes rheumatoid arthritis by enhancing Wnt7b mediated macrophage-FLS communication

  • 期刊论文

  • 发表日期：

    2026年7月3日

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  • Bing Wang,
  • Yingqiu Song,
  • Wenbo Xu,
  • Jiaqing Chen,
  • Yurong Huang,
  • Xinyue Zhou,
  • Yikang Cai,
  • Aixin Xia,
  • Yanping Li,
  • Liwei Jiang,
  • Faxue Liao,
  • Jian Huang,
  • Chenggui Miao

摘要

Background

Our previous research has shown that lipopolysaccharide (LPS) derived from Gram-negative bacteria in the intestine promoted rheumatoid arthritis (RA) after entering peripheral blood, but the specific molecular mechanism was unclear.

Method

This study used transcriptome and proteomic sequencing, western blotting, co-immunoprecipitation (Co-IP), cell co-culture, and other related methods to investigate whether LPS entering peripheral blood activated the Wnt7b secretion in macrophages, and used the Wnt7b as a messenger molecule to promote the communication between macrophage-fibroblast-like synoviocyte (FLSs), ultimately leading to the onset of RA.

Result

The results showed that LPS significantly promoted the pathology of collagen induced arthritis (CIA) mice. Transcriptome and proteomic sequencing, as well as experimental validation, confirmed that the target of LPS may be the Wnt7b. Knocking down the Wnt7b in CIA mice could effectively alleviate the LPS induced pathology. Furthermore, in the M0 macrophage-FLS co-culture system, overexpression of Wnt7b in M0 macrophages promoted the expression of RA pathological factors in FLSs and activated the WNT/CTNNB1 signaling pathway of FLSs. However, knocking down the Wnt7b in M1 macrophages resulted in the opposite effects. Interestingly, in the M0 macrophage-FLS co-culture system, overexpression of Wnt7b in M0 macrophages could enhance the expression of frizzled class receptor 8 (FZD8) on FLSs, activating the Wnt/β-catenin signaling pathway of FLSs. However, knocking down the FZD8 in FLSs after overexpression of Wnt7b could interfere with the effects of overexpression of Wnt7b. In addition, adding LPS to M0 macrophages promoted the FZD8 expression of co-cultured FLSs and activated the Wnt/β-catenin signaling pathway. Knocking down FZD8 in FLSs after adding LPS to M0 macrophages could interfere with the effects of LPS.

Conclusion

This study suggested that circulating LPS stimulated macrophages to secrete Wnt7b, which acted as a messenger molecule and bound to the FZD8 receptor on the FLSs cell membrane in the synovial microenvironment, promoting the activation of the Wnt/β-catenin signaling pathway in FLSs and leading to RA.