PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury

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 () and Zhaojun Wang ()
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Xinyue Du: Shanghai Jiao Tong University School of Medicine
Baiyang Ren: Shanghai Jiao Tong University School of Medicine
Chang Li: Shanghai Jiao Tong University School of Medicine
Qi Li: Shanghai Jiao Tong University School of Medicine
Shuo Kan: Shanghai Jiao Tong University School of Medicine
Xin Wang: Shanghai Jiao Tong University School of Medicine
Wenjuan Bai: Shanghai Jiao Tong University School of Medicine
Chenyun Wu: Shanghai Jiao Tong University School of Medicine
Kokouvi Kassegne: Shanghai Jiao Tong University School of Medicine
Huibo Yan: Shanghai Jiao Tong University School of Medicine
Xiaoyin Niu: Shanghai Jiao Tong University School of Medicine
Min Yan: Kunming Medical University
Wenyue Xu: Army Medical University (The Third Military Medical University)
Samuel C. Wassmer: London School of Hygiene & Tropical Medicine
Jing Wang: Shanghai Jiao Tong University School of Medicine
Guangjie Chen: Shanghai Jiao Tong University School of Medicine
Zhaojun Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45210-5

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