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Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus

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Abstract

Objective

microRNAs (miRNAs) play critical roles in embryogenesis, cell differentiation and the pathogenesis of several human diseases, including systemic lupus erythematosus (SLE). Toll-like receptors (TLRs) are also known to exert crucial functions in the immune response activation occurring in the pathogenesis of autoimmune diseases like SLE. Herein, the current study aimed to explore the potential role of miR-152-3p in TLR-mediated inflammatory response in SLE.

Methods

We determined the miR-152-3p expression profiles in CD4+ T cells and peripheral blood mononuclear cells (PBMCs) harvested from patients with SLE and healthy controls, and analyzed the correlation between miR-152-3p expression and clinicopathological parameters. CD70 and CD40L expression patterns in CD4+ T cells were assessed by RT-qPCR and flow cytometry. ChIP was adopted to determine the enrichment of DNA methyltransferase 1 (DNMT1) in the promoter region of myeloid differentiation factor 88 (MyD88).

Results

The obtained findings revealed that miR-152-3p was highly-expressed in CD4+ T cells and PBMCs of patients with SLE, and this high expression was associated with facial erythema, joint pain, double-stranded DNA, and IgG antibody. DNMT1 could be enriched in the MyD88 promoter, and miR-152-3p inhibited the methylation of MyD88 by targeting DNMT1. We also found that silencing miR-152-3p inhibited MyD88 expression not only to repress the autoreactivity of CD4+ T cells and but also to restrain their cellular inflammation, which were also validated in vivo.

Conclusion

Our study suggests that miR-152-3p promotes TLR-mediated inflammatory response in CD4+ T cells by regulating the DNMT1/MyD88 signaling pathway, which highlights novel anti-inflammatory target for SLE treatment.

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Data availability

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

miRNAs:

MicroRNAs

SLE:

Systemic lupus erythematosus

MyD88:

Myeloid differentiation factor 88

PBMCs:

Peripheral blood mononuclear cells

PB:

Peripheral blood

ELISA:

Enzyme linked-immunosorbent assay

MSP:

Methylation-specific PCR

CHIP:

Chromatin immunoprecipitation

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Acknowledgements

We give our sincere gratitude to the reviewers for their valuable suggestions.

Funding

This study is supported by the Project Program of Neurosurgical Clinical Research Center of Sichuan Province, Science and Technology Foundation of Luzhou (2015-S-45(2/5)), Science and Technology Foundation of Southwest Medical University (2017-ZRQN-180, 2017-ZRQN-110).

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Author notes

  1. Bei Tao and Wei Xiang contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Immunology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China

    Bei Tao & Chengsong He

  2. Department of Neurosurgery, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou, 646000, Sichuan Province, People’s Republic of China

    Wei Xiang, Xianglong Li, Ligang Chen, Xiangguo Xia, Tangming Peng, Lilei Peng, Xiaobo Yang & Chuanhong Zhong

  3. Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, 646000, People’s Republic of China

    Wei Xiang, Xianglong Li, Ligang Chen, Xiangguo Xia, Tangming Peng, Lilei Peng, Xiaobo Yang & Chuanhong Zhong

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  1. Bei Tao
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Contributions

BT and WX designed the study. XL and CH collated the data, conducted data analyses. LC, XX and TP completed the initial draft of the manuscript. LP, XY and CZ contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Chuanhong Zhong.

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Tao, B., Xiang, W., Li, X. et al. Regulation of Toll-like receptor-mediated inflammatory response by microRNA-152-3p-mediated demethylation of MyD88 in systemic lupus erythematosus. Inflamm. Res. 70, 285–296 (2021). https://doi.org/10.1007/s00011-020-01433-y

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