Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel
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 hydroxylas...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56403-x |
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| author | 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 Wuyang Wang |
| author_facet | 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 Wuyang Wang |
| author_sort | Yanhong Xing |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-880d5cc4d7474af2b6486d9f01184a91 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-880d5cc4d7474af2b6486d9f01184a912025-01-26T12:42:41ZengNature PortfolioNature Communications2041-17232025-01-0116112010.1038/s41467-025-56403-xLysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channelYanhong Xing0Meng-meng Wang1Feifei Zhang2Tianli Xin3Xinyan Wang4Rong Chen5Zhongheng Sui6Yawei Dong7Dongxue Xu8Xingyu Qian9Qixia Lu10Qingqing Li11Weijie Cai12Meiqin Hu13Yuqing Wang14Jun-li Cao15Derong Cui16Jiansong Qi17Wuyang Wang18Jiangsu 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 UniversityDepartment of Otolaryngology and Neck Surgery, Shengjing Hospital of China Medical UniversityJiangsu 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 UniversityJiangsu 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 UniversityJiangsu 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 UniversityThe First People’s Hospital of YanchengState Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong KongJiangsu 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 UniversityJiangsu 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 UniversityJiangsu 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 UniversityJiangsu 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 UniversityJiangsu 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 UniversityNew Cornerstone Science Laboratory, Liangzhu Laboratory & School of Basic Medical Sciences, Zhejiang UniversityNew Cornerstone Science Laboratory, Liangzhu Laboratory & School of Basic Medical Sciences, Zhejiang UniversityDepartment of Medicine and Biosystemic Science, Faculty of Medicine, Kyushu UniversityJiangsu 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 UniversityDepartment of Anesthesiology, The Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineGuangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Affiliated hospital of Guangdong Medical UniversityJiangsu 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 UniversityAbstract 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.https://doi.org/10.1038/s41467-025-56403-x |
| spellingShingle | 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 Wuyang Wang Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel Nature Communications |
| title | Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel |
| title_full | Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel |
| title_fullStr | Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel |
| title_full_unstemmed | Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel |
| title_short | Lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal Fe2+ through TRPML1 channel |
| title_sort | lysosomes finely control macrophage inflammatory function via regulating the release of lysosomal fe2 through trpml1 channel |
| url | https://doi.org/10.1038/s41467-025-56403-x |
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