Yue Hanwei, Shi Guiying, Tang Jiaming, Li Xinyue, Bai Lin
Institute of Laboratory Animal Science, CAMS & PUMC, National Human Diseases Animal Model Resource Center, National Center of Technology Innovation for animal model, Chao-Yang District, Beijing, 100021, China.
Cell Commun Signal. 2025 Jul 21;23(1):349. doi: 10.1186/s12964-025-02353-2.
As the diverse functions of neutrophils continue to be uncovered, elucidating the molecular mechanisms that regulate their differentiation, development, and apoptosis has become crucial for overcoming limitations in the treatment of neutrophil-related diseases. Hematopoietic cell-specific protein 1-associated protein X 1 (HAX1), encoded by the primary pathogenic gene of autosomal recessive severe congenital neutropenia, serves as a key target for in-depth exploration of neutrophil function. In the Hax1 myeloid knockout C57BL/6J mice and stably transduced HL-60 cells with HAX1 knockdown that we constructed, our results showed that the differentiation of granulocyte-monocyte precursor cells (GMPs) and the maturation of neutrophils were inhibited, significantly reducing the proportion of myeloid cells and neutrophils in both bone marrow and peripheral blood. In addition, HAX1 deletion disrupted mitochondrial structure and mitochondrial membrane potential in neutrophils and increased the protein levels of B-cell lymphoma 2 (BCL-2) family members and cleaved Caspase-9. Through RNA sequencing and mRNA validation, we further demonstrated that HAX1 regulates neutrophil apoptosis and maturation via the mitochondrial-mediated classical apoptotic pathway and toll-like receptor 2 (TLR2)-mediated purine-rich box 1 (PU.1) signaling. This study elucidated the critical role of HAX1 in neutrophil differentiation, maturation, and apoptosis, providing new targets for research into neutrophil-related diseases.
随着中性粒细胞的多种功能不断被揭示，阐明调节其分化、发育和凋亡的分子机制对于克服中性粒细胞相关疾病治疗中的局限性至关重要。常染色体隐性严重先天性中性粒细胞减少症的主要致病基因编码的造血细胞特异性蛋白1相关蛋白X1（HAX1），是深入探索中性粒细胞功能的关键靶点。在我们构建的Hax1髓系敲除C57BL/6J小鼠和稳定转导HAX1敲低的HL-60细胞中，我们的结果表明，粒细胞-单核细胞前体细胞（GMPs）的分化和中性粒细胞的成熟受到抑制，显著降低了骨髓和外周血中髓系细胞和中性粒细胞的比例。此外，HAX1缺失破坏了中性粒细胞的线粒体结构和线粒体膜电位，并增加了B细胞淋巴瘤2（BCL-2）家族成员和裂解的半胱天冬酶-9的蛋白水平。通过RNA测序和mRNA验证，我们进一步证明HAX1通过线粒体介导的经典凋亡途径和Toll样受体2（TLR2）介导的富含嘌呤盒1（PU.1）信号传导来调节中性粒细胞的凋亡和成熟。本研究阐明了HAX1在中性粒细胞分化、成熟和凋亡中的关键作用，为中性粒细胞相关疾病的研究提供了新的靶点。
