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Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn’s disease

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Abstract

Background

Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown.

Methods

CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting.

Results

CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs’ barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF.

Conclusions

Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

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Availability of data and materials

Data are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank for the support of the National Natural Science Foundation of China (81970449).

Funding

This work was partly supported by the National Natural Science Foundation of China (Grant 81970449).

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Author notes

  1. Weigang Shu and Yongheng Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, China

    Weigang Shu, Yongheng Wang, Zhuoma Deji, Chuanding Li & Xiaolei Wang

  2. Center for Difficult and Complicated Abdominal Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, 200072, China

    Chunqiu Chen

  3. Department of Colorectal Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China

    Wenjun Ding & Peng Du

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  1. Weigang Shu
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Contributions

Xiaolei Wang designed the study and critically revised the whole manuscript. Weigang Shu and Yongheng Wang were involved in the acquisition, analysis and interpretation of data, as well as the drafting of the manuscript and the drawing of all the figures. Chuanding Li, Deji Zhuoma and Chunqiu Chen, Wenjun Ding and Peng Du were involved in the acquisition and analysis of data for the work. All authors agree with the final approval of the version to be published.

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Correspondence to Xiaolei Wang.

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This study was approved by the Institutional Ethics Committee of Shanghai Tenth People's Hospital (SHSY-IEC-4.1/20-152/01).

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Shu, W., Wang, Y., Deji, Z. et al. Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn’s disease. Inflamm. Res. (2024). https://doi.org/10.1007/s00011-024-01889-2

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  • DOI: https://doi.org/10.1007/s00011-024-01889-2

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