A20/NLRP3介导巨噬细胞M1/M2极化在ITP发病机制中的作用

Thrombocytopenia is one of the pathogenesis of immune thrombocytopenia (ITP). Immature of megakaryocytes is critical role in thrombocytopenia. It is of great importance to further investigate ITP bone hematopoiesis niche, including mesenchymal stem cells (MSCs) and macrophage, into the pathogenesis of megakaryocyte (MK) maturation. Our previous study found that MSCs from ITP patients showed enhanced senescence and apoptosis, and aberrant higher macrophage M1/M2 polarization ratio was also found in ITP. The higher M1 polarization impaired the megakaryocyte maturation, PPF and platelet production in vitro in ITP. This project aim to explore the relationship between MSCs and macrophage polarization in bone marrow niche of ITP, and to reveal the abnormal A20/NLRP3 signaling pathway modulate the polarization of macrophage; to further study the role of macrophage polarization in megakaryocyte maturation and platelet production, and the details of its underlying mechanism. The core problem of our project is to explore the theories of ITP pathogenesis and finally, provide new potential targets and strategy for ITP.

血小板生成减少是免疫性血小板减少症（ITP）重要发病机制，而巨核细胞成熟障碍是血小板生成减少发病的核心步骤。ITP患者造血微环境间充质干细胞（MSCs）和巨噬细胞（Mφ）对巨核细胞成熟分化作用的研究，有重要的临床和理论意义。申请者在前期研究中发现ITP骨髓MSCs凋亡衰老增加，且ITP肝脏、脾脏及骨髓等巨噬细胞极化异常（M1/M2），进一步研究发现，ITP巨噬细胞极化影响巨核细胞凋亡和PPF形成，强烈提示：巨噬细胞极化对巨核细胞凋亡及分化发育有影响，这一新发现国内外未见报道。本课题拟通过体内外研究，探讨ITP骨髓MSCs影响巨噬细胞极化作用，研究A20/NLRP3信号通路介导巨噬细胞极化的分子机制，阐明ITP巨噬细胞极化在巨核细胞成熟及血小板生成中的关键作用，拓展ITP的巨核细胞凋亡和PPF功能障碍理论，为ITP防治提供潜在新靶点和新策略。

血小板生成减少是免疫性血小板减少症（ITP）重要发病机制，而巨核细胞成熟障碍是血小板生成减少发病的关键步骤。造血微环境中ITP间充质干细胞（MSCs）和巨噬细胞（Mφ）对巨核细胞成熟分化的作用的研究，有重要的临床和理论意义。申请者通过体内外研究发现，探讨ITP骨髓MSCs凋亡衰老增加，且MSCs影响巨噬细胞极化异常（M1/M2），该异常与A20/NLRP3信号通路相关，提示ITP巨噬细胞极化在巨核细胞成熟及血小板生成中的起关键作用，拓展ITP的巨核细胞凋亡和PPF功能障碍理论，为ITP的防治提供新靶点和新策略。