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Macrophage retrotransposon expression is associated with lupus

Genes & Immunity (2025)Cite this article

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Abstract

Genetic variants of NCF1 that impair the production of reactive oxygen species (ROS) are associated with lupus in humans; however, the underlying mechanism of immune dysregulation remains unclear. To clarify this mechanism, the study tested the hypothesis that retrotransposons contribute to the early onset of lupus by facilitating the expansion and activation of macrophages. Using the ROS-deficient lupus-prone lpr mouse model, we employed bulk RNA sequencing, flow cytometry, and spatially resolved single-cell transcriptome imaging to comprehensively characterize tissue-resident macrophages. The results demonstrated increased expression of the mouse transcript family type D (MTD) retrotransposon in tissue-resident macrophages from the spleen, kidneys, and skull dura of ROS-deficient lpr mice, indicating a link between ROS deficiency, MTD expression, and macrophage expansion. Importantly, this MTD expression decreased following two weeks of mycophenolate mofetil therapy, linking therapy response to retrotransposon activity. Furthermore, the MTD-encoded RNA was used to disrupt the signaling of retrotransposons, leading to regulatory T-cell activation and downregulation of both glomerular macrophage infiltration and serum interleukin-6 secretion in lupus-prone mice. Collectively, these findings suggest that the MTD retrotransposons play a crucial role in driving the early onset of lupus by enhancing macrophage activation, which in turn promotes immune dysregulation.

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Fig. 1: The Ncf1 polymorphism induces MTD expression in the blood.
Fig. 2: The Ncf1 polymorphism enhances the activation of monocytes/macrophages.
Fig. 3: The Ncf1 polymorphism led to a reduction in the regulatory CD4 T cells.
Fig. 4: The Ncf1 polymorphism enhances the activation of renal macrophages.
Fig. 5: The Ncf1 polymorphism led to an increase in macrophages in the skull dura.
Fig. 6: RNA delivery alleviated the CEBPB signaling.
Fig. 7: RNA delivery alleviated the IL-6 secretion and macrophage infiltration.
Fig. 8: An overview of MTD retrotransposon signaling in lupus.

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Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information file].

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Acknowledgements

This work was supported in part by the Beijing Natural Science Foundation [IS23113, L222141, 7252286, J2023010], the National Natural Science Foundation of China [62027901], and the Fundamental Research Funds for the Central Universities [YWF23YG-QB015].

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Authors and Affiliations

  1. School of Engineering Medicine, Beihang University, Beijing, China

    Jianghong Zhong, Zhongheng Chen, Hangqi Yue, Zhicheng Han & Weibin Zhu

  2. Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology, Beijing, China

    Jianghong Zhong, Zhongheng Chen, Hangqi Yue, Zhicheng Han & Weibin Zhu

  3. School of Biological Science and Medical Engineering, Beihang University, Beijing, China

    Hangqi Yue & Zhicheng Han

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Contributions

JZ designed and supervised the study, analyzed the data, and wrote the manuscript. ZC performed the experiments, analyzed the data, and revised the paper. HY, ZH, and WZ performed the experiments. All authors read and approved the final manuscript.

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Correspondence to Jianghong Zhong.

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The animal study protocols were approved by the ethical committees of Beihang University, China (BM20210060). All animal models and experimental procedures were performed in accordance with standard laboratory guidelines, institutional biosafety regulations, and manufacturer’s recommendations. No primary human tissues, human subjects, or cell lines were involved in this research.

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Zhong, J., Chen, Z., Yue, H. et al. Macrophage retrotransposon expression is associated with lupus. Genes Immun (2025). https://doi.org/10.1038/s41435-025-00369-9

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