Guo Xin, Lei Yunxuan, Xu Yanhua, Du Xinyue, Lin Lin, Luo Yanping, Xi Yebin, Guo Yinshi, Niu Xiaoyin, Wang Zhaojun, Chen Guangjie
Department of Immunology and Microbiology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Allergy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2025 Apr 21;16(1):322. doi: 10.1038/s41419-025-07649-2.
Mast cells play a central role in allergic reactions, acting as key effector cells that initiate and amplify the inflammatory response. In this study, we demonstrate that phosphatase of regenerating liver 2 (PRL2) functions as a negative regulator of FcεRI-mediated mast cell activation. In PRL2-deficient myeloid cells, PRL2 conditional knockout mice developed more severe passive systemic anaphylaxis (PSA). Although PRL2 deficiency does not impact mast cell development, in the absence of PRL2 FcεRI-mediated mast cell activation is enhanced. In the presence of IgE the expression of mast cell PRL2 is downregulated, leading to modulation of the cellular response. In PRL2-deficient mast cells, the PI3K signaling pathway is upregulated, resulting in increased calcium influx. This, in turn, enhances mast cell degranulation and the production of inflammatory mediators. Moreover, hydroxychloroquine (an inhibitor of PRL2 degradation) reduces the severity of PSA in wild-type mice. Our findings suggest that PRL2 acts as a negative regulator of FcεRI-mediated mast cell activation. Therefore, therapeutic strategies aimed at enhancing PRL2 activity in mast cells may offer a promising approach for the treatment of allergic disorders.
肥大细胞在过敏反应中起核心作用，作为启动和放大炎症反应的关键效应细胞。在本研究中，我们证明再生肝脏磷酸酶2（PRL2）作为FcεRI介导的肥大细胞活化的负调节因子发挥作用。在PRL2缺陷的髓样细胞中，PRL2条件性敲除小鼠发生更严重的被动全身过敏反应（PSA）。虽然PRL2缺陷不影响肥大细胞发育，但在缺乏PRL2的情况下，FcεRI介导的肥大细胞活化增强。在存在IgE的情况下，肥大细胞PRL2的表达下调，导致细胞反应的调节。在PRL2缺陷的肥大细胞中，PI3K信号通路上调，导致钙内流增加。这反过来又增强了肥大细胞脱颗粒和炎症介质的产生。此外，羟氯喹（一种PRL2降解抑制剂）降低了野生型小鼠中PSA的严重程度。我们的研究结果表明PRL2作为FcεRI介导的肥大细胞活化的负调节因子发挥作用。因此，旨在增强肥大细胞中PRL2活性的治疗策略可能为治疗过敏性疾病提供一种有前景的方法。
