PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury
Abstract Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasm...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45210-5 |
| _version_ | 1797273907016761344 |
|---|---|
| author | Xinyue Du Baiyang Ren Chang Li Qi Li Shuo Kan Xin Wang Wenjuan Bai Chenyun Wu Kokouvi Kassegne Huibo Yan Xiaoyin Niu Min Yan Wenyue Xu Samuel C. Wassmer Jing Wang Guangjie Chen Zhaojun Wang |
| author_facet | Xinyue Du Baiyang Ren Chang Li Qi Li Shuo Kan Xin Wang Wenjuan Bai Chenyun Wu Kokouvi Kassegne Huibo Yan Xiaoyin Niu Min Yan Wenyue Xu Samuel C. Wassmer Jing Wang Guangjie Chen Zhaojun Wang |
| author_sort | Xinyue Du |
| collection | DOAJ |
| description | Abstract Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease. |
| first_indexed | 2024-03-07T14:50:50Z |
| format | Article |
| id | doaj.art-ba5b3b99873e4f85a3a2d67ae8d2f9be |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:50:50Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ba5b3b99873e4f85a3a2d67ae8d2f9be2024-03-05T19:43:09ZengNature PortfolioNature Communications2041-17232024-01-0115111410.1038/s41467-024-45210-5PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injuryXinyue Du0Baiyang Ren1Chang Li2Qi Li3Shuo Kan4Xin Wang5Wenjuan Bai6Chenyun Wu7Kokouvi Kassegne8Huibo Yan9Xiaoyin Niu10Min Yan11Wenyue Xu12Samuel C. Wassmer13Jing Wang14Guangjie Chen15Zhaojun Wang16Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineKey Laboratory of Parasite and Vector Biology, Ministry of Health, China; School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineDepartment of Pathogen Biology and Immunology, Faculty of Basic Medical Science, Kunming Medical UniversityDepartment of Pathogenic Biology, Army Medical University (The Third Military Medical University)Department of Infection Biology, London School of Hygiene & Tropical MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineShanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of MedicineAbstract Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.https://doi.org/10.1038/s41467-024-45210-5 |
| spellingShingle | Xinyue Du Baiyang Ren Chang Li Qi Li Shuo Kan Xin Wang Wenjuan Bai Chenyun Wu Kokouvi Kassegne Huibo Yan Xiaoyin Niu Min Yan Wenyue Xu Samuel C. Wassmer Jing Wang Guangjie Chen Zhaojun Wang PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury Nature Communications |
| title | PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| title_full | PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| title_fullStr | PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| title_full_unstemmed | PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| title_short | PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| title_sort | prl2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury |
| url | https://doi.org/10.1038/s41467-024-45210-5 |
| work_keys_str_mv | AT xinyuedu prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT baiyangren prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT changli prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT qili prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT shuokan prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT xinwang prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT wenjuanbai prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT chenyunwu prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT kokouvikassegne prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT huiboyan prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT xiaoyinniu prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT minyan prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT wenyuexu prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT samuelcwassmer prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT jingwang prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT guangjiechen prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury AT zhaojunwang prl2regulatesneutrophilextracellulartrapformationwhichcontributestoseveremalariaandacutelunginjury |