2. Academic Validation
  3. Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel

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

  • Nat Commun. 2025 Jan 24;16(1):985. doi: 10.1038/s41467-025-56403-x.
Yanhong Xing # 1,  Meng-Meng Wang # 2,  Feifei Zhang # 1,  Tianli Xin # 1,  Xinyan Wang 1,  Rong Chen 3,  Zhongheng Sui 4,  Yawei Dong 1,  Dongxue Xu 1,  Xingyu Qian 1,  Qixia Lu 1,  Qingqing Li 1,  Weijie Cai 5,  Meiqin Hu 5 6,  Yuqing Wang 7,  Jun-Li Cao 8,  Derong Cui 9,  Jiansong Qi 10,  Wuyang Wang 11
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2 Department of Otolaryngology and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
  • 3 The First People's Hospital of Yancheng, Yancheng, China.
  • 4 State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, Hong Kong, China.
  • 5 New Cornerstone Science Laboratory, Liangzhu Laboratory & School of Basic Medical Sciences, Zhejiang University, Hangzhou, China.
  • 6 Department of Neurology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 7 Department of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu University, Fukuoka, Kyushu, Japan.
  • 8 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China. caojl0310@aliyun.com.
  • 9 Department of Anesthesiology, The Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. cuishuning118@163.com.
  • 10 Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated hospital of Guangdong Medical University, Zhanjiang, Guangdong, China. Maggie.qi@dal.ca.
  • 11 Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China. wuyangwang80@gmail.com.
  • # Contributed equally.
PMID: 39856099 DOI: 10.1038/s41467-025-56403-x
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.

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