A novel role for endoplasmic reticulum protein ERp72 in the pathogenesis of autoantibody-induced arthritis

Abstract

Objective

The family of protein disulphide isomerases (PDIs) is a group of oxidoreductases that catalyze the oxidation, reduction and isomerization of disulphide bonds. Recent studies have shown that overexpression of one of the family enzymes, ERp46, potentiates arthritis severity, suggesting that the PDI family participates in arthritis pathogenesis. This study investigated the role of another PDI member, ERp72, in autoantibody-induced arthritis.

Methods

Using the Cre-LoxP method, a mouse strain lacking ERp72 (ERp72^−/− mice) was generated. Autoantibody-induced arthritis was induced in both ERp72^−/− and ERp72^+/+ control mice by injecting serum from K/BxN mice. The synovial inflammation severity was evaluated by joint diameter measurements and histological analysis. Proinflammatory cytokines expression in joint tissue and plasma was assessed by quantitative real-time PCR and ELISA.

Results

: The absence of ERp72 in the joints, white blood cells, spleen, thymus, and bone marrow of ERp72^−/− mice was confirmed. In the K/BxN serum transfer-induced arthritis (STIA) model, ERp72^−/− mice exhibited exacerbated arthritis compared to ERp72^+/+ mice, with greater joint swelling, bone and cartilage erosion, and synovial inflammation. Furthermore, ERp72^–/– mice exhibited increased expression of IL-1β, IL-6 and TNF-α in inflamed joint tissues and higher IL-6 levels in plasma. Conversely, IL-10 levels were lower in ERp72^–/– mice inflamed joints than in ERp72^+/+ mice. Notably, the basal TNF-α level in the blood of ERp72^−/− mice was significantly higher than in ERp72^+/+ mice.

Conclusion

ERp72 plays a key role in the negative regulation of autoantibody-induced arthritis.

Acknowledgement

We thank Dr Christophe Benoist for providing the KRN T-cell receptor transgenic mice.

Disclosure statement

No potential conflict of interest was reported by the authors.

Compliance with ethical standards

Research involving human participants and/or animals: This article does not contain any studies with human participants. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/03009742.2024.2362040

Additional information

Funding

This research was supported by grants from the National Natural Science Foundation of China [82200147, 81770138, 81970128, 82270136 and 31970890], the China Postdoctoral Science Foundation [2021TQ0231 and 2022M722322], the Jiangsu Funding Program for Excellent Postdoctoral Talent, the Translational Research Grant of NCRCH [2020ZKPA02 and 2020WSA04], the collaboration fund from the State Key Laboratory of Radiation Medicine and Protection [GZN1201802], and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).