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IL-38, a potential therapeutic agent for lupus, inhibits lupus progression

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Abstract

Background

Previous studies reported that IL-38 was abnormally expressed in patients with systemic lupus erythematosus (SLE). However, the involvement of IL-38 in the pathophysiology of SLE remains unknown.

Methods

The therapeutic potential of IL-38 was tested in pristane-treated wild-type (WT) and IL-38−/− mice. Thus, SLE was induced via pristane in WT and IL-38−/− mice. Afterwards, the liver, spleen, and kidney of each mouse were obtained. The flow cytometric analysis of the immune cells, serologic expression of inflammatory cytokines and autoantibodies, renal histopathology, and inflammatory signaling were evaluated.

Results

WT mice with pristane-induced lupus exhibited hepatomegaly, splenomegaly, severe kidney damages, increased lymphoproliferation, enhanced lymphoproliferation, and upregulated inflammatory cytokines, such as IL-6, IL-13, IL-17A, MIP-3α, IL-12p70, and IFNγ, and elevated levels of autoantibodies, such as ANA IgG, anti-dsDNA IgG, and total IgG. IL-38−/− mice whose lupus progressed, had elevated cells of CD14+, CD19+, CD3+, and Th1, upregulated inflammatory cytokines and autoantibodies, and severe pathological changes in kidney. Administration of recombinant murine IL-38 to pristane-treated IL-38−/− mice improved their renal histopathology, which depended on ERK1/2, JNK1/2, p38, NF-κB p65, and STAT5 signaling pathways.

Conclusion

IL-38 regulates SLE pathogenesis. Furthermore, targeting IL-38 is critical in the treatment of SLE.

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Data availability

Datasets are available from the corresponding author on reasonable request.

Abbreviations

SLE:

Systemic lupus erythematosus

WT:

Wild-type

IL-38:

Interleukin-38

LN:

Lupus nephritis

IL-1Ra:

IL-1 receptor antagonist

IL-36Ra:

IL-36 receptor antagonist

RA:

Rheumatoid arthritis

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81701606), and Sichuan Provincial Natural Science Foundation (2022NSFSC0697, 2022NSFSC0694).

Author information

Author notes

  1. Wang-Dong Xu and Lin-Chong Su contributed equally to this work.

Authors and Affiliations

  1. Department of Evidence-Based Medicine, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China

    Wang-Dong Xu, Xiao-Yan Liu, Qi Huang, Qian Wu & Jie Zhou

  2. Department of Rheumatology and Immunology, Minda Hospital of Hubei Minzu University, 2 Wufengshan Road, Enshi, 445000, Hubei, China

    Lin-Chong Su

  3. Laboratory Animal Center, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China

    Lu Fu

  4. Department of Rheumatology and Immunology, Affiliated Hospital of Southwest Medical University, 25 Taiping road, Luzhou, 646000, Sichuan, China

    You-Yu Lan & An-Fang Huang

Authors
  1. Wang-Dong Xu
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  9. An-Fang Huang
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Contributions

Study conception and design: WX, LS, and AH. Acquisition of data: LF, YL, and XL. Analysis and interpretation of data: QH, QW, and JZ. Drafting the article: WX, LS, and AH. Final approval of the version of the article to be published: all the authors, and all the authors agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to An-Fang Huang.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

This study was approved Animal Ethics Committee of Southwest Medical University.

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Responsible Editor: John Di Battista.

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Xu, WD., Su, LC., Fu, L. et al. IL-38, a potential therapeutic agent for lupus, inhibits lupus progression. Inflamm. Res. 71, 963–975 (2022). https://doi.org/10.1007/s00011-022-01581-3

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  • DOI: https://doi.org/10.1007/s00011-022-01581-3

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