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

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 Wang, Jun-li Cao (), Derong Cui (), Jiansong Qi () and Wuyang Wang ()
Additional contact information
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
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

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56403-x

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