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Interferon-γ enhances the immunosuppressive ability of canine bone marrow-derived mesenchymal stem cells by activating the TLR3-dependent IDO/kynurenine pathway

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Abstract

Background

The immunomodulatory function of mesenchymal stem cells (MSCs) has been considered to be vital for MSC-based therapies. Many works have been devoted to excavate effective strategies for enhancing the immunomodulation effect of MSCs. Nonetheless, canine MSC-mediated immunomodulation is still poorly understood.

Methods and results

The inflammatory microenvironment was simulated through the employment of interferon-γ (IFN-γ) in a culture system. Compared with unstimulated cBMSCs, IFN-γ stimulation increased the mRNA levels of Toll-like receptor 3 (TLR3) and indoleamine 2, 3-dioxygenase 1 (IDO-1), and simultaneously enhanced the secretion of immunosuppressive molecules, including interleukin (IL)-10, hepatocyte growth factor (HGF), and kynurenine in cBMSCs. IFN-γ stimulation significantly enhanced the ability of cBMSCs and their supernatant to suppress the proliferation of murine spleen lymphocytes. Lymphocyte subtyping evaluation revealed that cBMSCs and their supernatant diminished the percentage of CD3+CD4+ and CD3+CD8+ lymphocytes compared with the control group, with a decreasing CD4+/CD8+ ratio. Notably, exposure to IFN-γ decreased the CD4+/CD8+ ratio more effectively than unstimulated cells or supernatant. Additionally, IFN-γ-stimulation increased the mRNA levels of the Th1 cytokines TNF-α, and remarkably decreased the mRNA level of the Th2 cytokine IL-4 and IL-10.

Conclusion

Our findings substantiate that IFN-γ stimulation can enhance the immunomodulatory properties of cBMSCs by promoting TLR3-dependent activation of the IDO/kynurenine pathway, increasing the secretion of immunoregulatory molecules and strengthening interactions with T lymphocytes, which may provide a meaningful strategy for the clinical application of cBMSCs in immune-related diseases.

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Data availability

Data are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors appreciate the experimental equipment support provided by Sichuan Agricultural University. Thanks are also due to Liping Yang for taking care of the animals used in this work.

Funding

This work was funded by the dual support plan for discipline construction of Sichuan. Agricultural University (035/2121993256).

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  1. Jiaqiang Deng, Danting Li and Xiaoya Huang have contributed equally to this work.

Authors and Affiliations

  1. College of Veterinary Medicine, Sichuan Agricultural University, 211 Huimin Road, Wenjiang District, Chengdu, 611130, Sichuan, China

    Jiaqiang Deng, Danting Li, Xiaoya Huang, Weiyao Li, Fangfang Zhao, Congwei Gu, Liuhong Shen, Suizhong Cao, Zhihua Ren, Zhicai Zuo, Junliang Deng & Shumin Yu

  2. Laboratory Animal Centre, Southwest Medical University, Luzhou, 646000, China

    Congwei Gu

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Contributions

JQD, DTL, and XYH: made substantial contributions to the conception and design of the study, acquisition of data, analysis and interpretation of data. JQD, DTL, XYH, WYL, FFZ, and CWG: contributed to manuscript preparation. LHS, SZC, ZHR, ZCZ, JLD, and SMY: gave critical revision for important intellectual content and final approval for the manuscript.

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Correspondence to Shumin Yu.

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This study was approved by the Faculty Animal Care and Use Committee of Sichuan Agricultural University (Ya’an, China; Approval No.2013–028) for the use of animals in this research.

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Deng, J., Li, D., Huang, X. et al. Interferon-γ enhances the immunosuppressive ability of canine bone marrow-derived mesenchymal stem cells by activating the TLR3-dependent IDO/kynurenine pathway. Mol Biol Rep 49, 8337–8347 (2022). https://doi.org/10.1007/s11033-022-07648-y

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