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Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription

Cell Death & Differentiation volume 30, pages 1279–1292 (2023)Cite this article

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Abstract

Macrophages play a critical role in the immune homeostasis and host defense against invading pathogens. However, uncontrolled activation of inflammatory macrophages leads to tissue injury and even fuels autoimmunity. Hence the molecular mechanisms underlying macrophage activation need to be further elucidated. The effects of epigenetic modifications on the function of immune cells draw increasing attention. Here, we demonstrated that lysine-specific demethylase 5B (KDM5B), a classical transcriptional repressor in stem cell development and cancer, was required for the full activation of NF-κB signaling cascade and pro-inflammatory cytokine production in macrophages. KDM5B deficiency or inhibitor treatment protected mice from immunologic injury in both collagen-induced arthritis (CIA) model and endotoxin shock model. Genome-wide analysis of KDM5B-binding peaks identified that KDM5B was selectively recruited to the promoter of Nfkbia, the gene encoding IκBα, in activated macrophages. KDM5B mediated the H3K4me3 modification erasing and decreased chromatin accessibility of Nfkbia gene locus, coordinating the elaborate suppression of IκBα expression and the enhanced NF-κB-mediated macrophage activation. Our finding identifies the indispensable role of KDM5B in macrophage-mediated inflammatory responses and provides a candidate therapeutic target for autoimmune and inflammatory disorders.

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Fig. 1: KDM5B deficiency ameliorates the immune injury and disease severity in mouse CIA model.
Fig. 2: KDM5B deficiency inhibits LPS-induced systemic inflammation in vivo.
Fig. 3: KDM5B is required for TLR-triggered pro-inflammatory cytokine production.
Fig. 4: KDM5B selectively promotes the activation of TLR-triggered NF-κB signaling.
Fig. 5: KDM5B-specific inhibitor GSK467 suppresses NF-κB-mediated inflammatory responses.
Fig. 6: KDM5B selectively inhibits the transcription of Nfkbia gene.
Fig. 7: KDM5B specifically binds to the Nfkbia promoter for regulating H3K4me3 modification and chromatin accessibility.

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Data availability

Data supporting the present study are available from the corresponding author upon reasonable request. Original images of unprocessed immunoblot and tissue staining are available at Supplementary information.

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Funding

Funding

This work was supported by the National Key R&D Program of China (2019YFA0801502), the National Natural Science Foundation of China (82071790, 82070415, 82271797), the Shuguang Program sponsored by the Shanghai Education Development Foundation and Shanghai Municipal Education Commission (18SG33, 19SG17), and the China National Postdoctoral Program for Innovative Talents (BX2021046).

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Author notes

  1. These authors contributed equally: Yunkai Zhang, Ying Gao, Yuyu Jiang.

Authors and Affiliations

  1. Department of Pathogen Biology, Naval Medical University, Shanghai, 200433, China

    Yunkai Zhang, Yuyu Jiang, Yingying Ding, Huiying Chen, Yan Xiang & Xingguang Liu

  2. National Key Laboratory of Medical Immunology, Naval Medical University, Shanghai, 200433, China

    Yunkai Zhang & Xingguang Liu

  3. Department of Rheumatology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China

    Ying Gao

  4. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Ying Gao & Zhenzhen Zhan

  5. Department of Liver Surgery, Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China

    Zhenzhen Zhan

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Contributions

YZ, YG, YJ, YD, HC and YX performed the experiments, analyzed the data, and interpreted the results. YZ drafted the manuscript. XL and ZZ conceived the idea, designed the experiments, assisted data analyses, revised the manuscript, and provided funding for this study. All authors read and approved the final manuscript.

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All experiments with animals were approved by the Animal Ethics Committee of Naval Medical University. All studies involving human PBMC samples were approved by the Medical Ethics Committee of Naval Medical University.

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Zhang, Y., Gao, Y., Jiang, Y. et al. Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell Death Differ 30, 1279–1292 (2023). https://doi.org/10.1038/s41418-023-01136-x

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