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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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.
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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