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Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel

Author

Listed:
  • Yanhong Xing

    (Xuzhou Medical University)

  • Meng-meng Wang

    (Shengjing Hospital of China Medical University)

  • Feifei Zhang

    (Xuzhou Medical University)

  • Tianli Xin

    (Xuzhou Medical University)

  • Xinyan Wang

    (Xuzhou Medical University)

  • Rong Chen

    (The First People’s Hospital of Yancheng)

  • Zhongheng Sui

    (University of Hong Kong)

  • Yawei Dong

    (Xuzhou Medical University)

  • Dongxue Xu

    (Xuzhou Medical University)

  • Xingyu Qian

    (Xuzhou Medical University)

  • Qixia Lu

    (Xuzhou Medical University)

  • Qingqing Li

    (Xuzhou Medical University)

  • Weijie Cai

    (Zhejiang University)

  • Meiqin Hu

    (Zhejiang University
    The Second Affiliated Hospital of Zhejiang University School of Medicine)

  • Yuqing Wang

    (Kyushu University)

  • Jun-li Cao

    (Xuzhou Medical University)

  • Derong Cui

    (The Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • Jiansong Qi

    (Affiliated hospital of Guangdong Medical University)

  • Wuyang Wang

    (Xuzhou Medical University)

Abstract

Lysosomes are best known for their roles in inflammatory responses by engaging in autophagy to remove inflammasomes. Here, we describe an unrecognized role for the lysosome, showing that it finely controls macrophage inflammatory function by manipulating the lysosomal Fe2+—prolyl hydroxylase domain enzymes (PHDs)—NF-κB—interleukin 1 beta (IL1B) transcription pathway that directly links lysosomes with inflammatory responses. TRPML1, a lysosomal cationic channel, is activated secondarily to ROS elevation upon inflammatory stimuli, which in turn suppresses IL1B transcription, thus limiting the excessive production of IL-1β in macrophages. Mechanistically, the suppression of IL1B transcription caused by TRPML1 activation results from its modulation on the release of lysosomal Fe2+, which subsequently activates PHDs. The activated PHDs then represses transcriptional activity of NF-κB, ultimately resulting in suppressed IL1B transcription. More importantly, in vivo stimulation of TRPML1 ameliorates multiple clinical signs of Dextran sulfate sodium-induced colitis in mice, suggesting TRPML1 has potential in treating inflammatory bowel disease.

Suggested Citation

  • Yanhong Xing & Meng-meng Wang & Feifei Zhang & Tianli Xin & Xinyan Wang & Rong Chen & Zhongheng Sui & Yawei Dong & Dongxue Xu & Xingyu Qian & Qixia Lu & Qingqing Li & Weijie Cai & Meiqin Hu & Yuqing W, 2025. "Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56403-x
    DOI: 10.1038/s41467-025-56403-x
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