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Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNβ1 transcription during macrophage activation

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Abstract

Background

As an anti-inflammatory cytokine, interleukin 10 (IL-10) plays a vital role in preventing inflammatory and autoimmune pathologies while also maintaining immune homeostasis. IL-10 production in macrophages is tightly regulated by multiple pathways. TRIM24, a member of the Transcriptional Intermediary Factor 1 (TIF1) family, contributes to antiviral immunity and macrophage M2 polarization. However, the role of TRIM24 in regulating IL-10 expression and its involvement in endotoxic shock remains unclear.

Methods

In vitro, bone marrow derived macrophages cultured with GM-CSF or M-CSF were stimulated with LPS (100ng/ml). Murine models of endotoxic shock were established by challenging the mice with different dose of LPS (i.p). RTPCR, RNA sequencing, ELISA and hematoxylin and eosin staining were performed to elucidate the role and mechanisms of TRIM24 in endotoxic shock.

Results

The expression of TRIM24 is downregulated in LPS-stimulated bone marrow-derived macrophages (BMDMs). Loss of TRIM24 boosted IL-10 expression during the late stage of LPS-stimulation in macrophages. RNA-seq analysis revealed the upregulation of IFNβ1, an upstream regulator of IL-10, in TRIM24 knockout macrophages. Treatment with C646, a CBP/p300 inhibitor, diminished the difference in both IFNβ1 and IL-10 expression between TRIM24 knockout and control macrophages. Loss of TRIM24 provided protection against LPS-induced endotoxic shock in mice.

Conclusion

Our results demonstrated that inhibiting TRIM24 promoted the expression of IFNβ1 and IL-10 during macrophage activation, therefore protecting mice from endotoxic shock. This study offers novel insights into the regulatory role of TRIM24 in IL-10 expression, making it a potentially attractive therapeutic target for inflammatory diseases.

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Data availability

The data sets used for the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Chun Guo, Jiajia Wang, Yanwei Li and Yingying Huang from the core facility platform of Zhejiang University School of Medicine for their technical support.

Funding

This work was supported in part by grants from the National Natural Science Foundation of China (31900638, 31970555, 32070630 and 32100477), the University-level scientific research project of Ningxia Medical University (XT2022006), the National Key R&D Project of China (2018YFA0800102) and the Zhejiang Innovation Team Grant (2020R01006).

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Author notes

  1. Zhaoyuan Hui, Yuanzheng Fu and Yunyun Chen contributed equally.

Authors and Affiliations

  1. Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, Zhejiang, China

    Zhaoyuan Hui, Yuanzheng Fu, Yunyun Chen, Jie Yin, Hui Fang, Yifan Tu, Ying Gu & Jiawei Zhang

  2. Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, 750004, China

    Zhaoyuan Hui

  3. Department of Genetics, Institute of Genetics, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Zhaoyuan Hui, Yuanzheng Fu, Yunyun Chen, Jie Yin, Hui Fang, Yifan Tu & Ying Gu

  4. Zhejiang Provincial Key Lab of Genetic and Developmental Disorder, Hangzhou, 310058, Zhejiang, China

    Ying Gu

  5. Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 311121, China

    Ying Gu

  6. Ningxia Key Laboratory of Prevention and Control of Common Infectious Diseases, Yinchuan, 750004, China

    Zhaoyuan Hui

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Contributions

YG, JZ and ZH designed the research. ZH, YF, YC, HF and YT performed the experiments. JY performed the analysis of RNA-seq. ZH, JZ and YG wrote the manuscript. JZ and YG supervised the project.

Corresponding authors

Correspondence to Ying Gu or Jiawei Zhang.

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The authors declare no competing financial interests.

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All mouse experiments were approved by the Institutional Animal Care and Use Committee and were in strict accordance with good animal practice as defined by the Zhejiang University Laboratory Animal Center (AP CODE: ZJU20220255).

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Hui, Z., Fu, Y., Chen, Y. et al. Loss of TRIM24 promotes IL-10 expression via CBP/p300-dependent IFNβ1 transcription during macrophage activation. Inflamm. Res. 72, 1441–1452 (2023). https://doi.org/10.1007/s00011-023-01751-x

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  • DOI: https://doi.org/10.1007/s00011-023-01751-x

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