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β-Indole-3-acetic acid attenuated collagen-induced arthritis through reducing the ubiquitination of Foxp3 via the AhR-TAZ-Tip60 pathway

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Abstract

Massive evidence shows that intestinal tryptophan metabolites affected by intestinal flora can modulate the progression of rheumatoid arthritis (RA). However, the effects and mechanisms of intestinal tryptophan metabolites on RA are not yet detailed. Herein, we investigated the protective effects of intestinal tryptophan metabolites on RA and its detailed mechanisms. In this study, the collagen-induced arthritis (CIA) rat model was established. Based on metabolomics analysis, the contents of β-indole-3-acetic acid (IAA), indolylpropionic acid, and indole-3-β-acrylic acid in the sera of CIA rats were significantly less compared with those of the normal rats. Under the condition of Treg or Th17 cell differentiation, IAA significantly promoted the differentiation and activation of Treg cells instead of Th17 cells. Intestinal tryptophan metabolites are well-known endogenic ligands of aryl hydrocarbon receptor (AhR). Not surprisingly, IAA increased the level of Foxp3 through activating the AhR pathway. Interestingly, IAA had little impact on the level of Foxp3 mRNA, but reducing the ubiquitination and degradation of Foxp3. Mechanically, IAA reduced the expression of the transcriptional coactivator TAZ, which was almost completely reversed by either AhR antagonist CH223191 or siRNA. In vitro, IAA decreased the combination of TAZ and the histone acetyltransferase Tip60, while it increased the combination of Tip60 and Foxp3. In CIA rats, oral administration of IAA increased the number of Treg cells and relieved the inflammation. A combined use with CH223191 almost abolished the effect of IAA. Taken together, IAA attenuated CIA by promoting the differentiation of Treg cells through reducing the ubiquitination of Foxp3 via the AhR-TAZ-Tip60 pathway.

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Funding

This study was supported by the National Natural Science Foundation of China (81903883), the Colleges and Universities in Hebei Province Science and Technology Research Project (BJK2022014), and the Natural Science Foundation of Hebei Province (H2023423121).

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Authors and Affiliations

  1. Department of Chinese Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China

    Xiaoran Su & Yajie Sun

  2. Department of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China

    Xinliu Wang & Xin Zhang

  3. Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China

    Yugai Jia

  4. Hebei International Cooperation Center for Ion Channel Function and Innovative Traditional Chinese Medicine, Shijiazhuang, 050091, China

    Yugai Jia

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  1. Xiaoran Su
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  3. Xin Zhang
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  4. Yajie Sun
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by XRS, XLW, XZ, and YJS. The first draft of the manuscript was written by XRS and YGJ. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yugai Jia.

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This article does not contain any studies with human participants by any of the authors. In this experiment, we did not collect any samples of human. The animals used in this paper were conducted under the guidelines of current ethical regulations for institutional animal care and use at Hebei University of Traditional Chinese Medicine (animal ethics was reviewed by the Experimental Animal Welfare Ethics Committee of Hebei University of Chinese Medicine, with ethical number DWLL202202009).

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Su, X., Wang, X., Zhang, X. et al. β-Indole-3-acetic acid attenuated collagen-induced arthritis through reducing the ubiquitination of Foxp3 via the AhR-TAZ-Tip60 pathway. Immunol Res (2024). https://doi.org/10.1007/s12026-024-09480-x

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