Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Institute of Modern Aquaculture Science and Engineering, School of Life Sciences, South China Normal University, Guangzhou, China.
Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.
J Immunol. 2024 Dec 1;213(11):1676-1690. doi: 10.4049/jimmunol.2300562.
Chemokines play crucial roles in the regulation of immune cell migration and development. The CXCL12/CXCR4 axis has been extensively studied in mammals, but its regulatory mechanism in teleost fish remains unclear. In this study, we used Nile tilapia (Oreochromis niloticus) as a teleost model to investigate the mediation of the CXCL12/CXCR4 axis in IgM+ B cells. Our findings demonstrate that the CXCL12/CXCR4 axis exhibits chemotactic activity on IgM+ B cells and promotes the phagocytosis of IgM+ B cells. Blocking CXCR4 severely impairs the chemotaxis and phagocytosis of IgM+ B cells in vitro and reduces the percentages and numbers of IgM+ B cells that migrate to peripheral blood after pathogen infection in vivo. This reduction in migration leads to a decrease in the inflammatory response, an increase in tissue bacterial load, and a decrease in survival rate. We also discovered that the evolutionarily conserved PI3K-AKT signaling pathway and Girdin are involved in the immune response during Streptococcus agalactiae infection. Inhibitors of the PI3K-AKT signaling pathway prevent the chemotaxis and phagocytosis of IgM+ B cells, impair the expression and phosphorylation levels of related proteins in vitro, and prevent IgM+ B cells chemotaxis into the peripheral blood after pathogen infection in vivo. Furthermore, CXCR4 blocking significantly downregulates the expression of AKT and Girdin. Overall, our study reveals the regulatory mechanism of the CXCL12/CXCR4 axis on IgM+ B cells via the PI3K-AKT signaling pathway in tilapia, suggesting that the functions of the CXCL12/CXCR4 axis in B cells may be conserved between mammals and teleost fish.
趋化因子在调节免疫细胞迁移和发育中发挥着关键作用。CXCL12/CXCR4 轴在哺乳动物中得到了广泛的研究，但在硬骨鱼类中的调控机制尚不清楚。在这项研究中，我们以尼罗罗非鱼（Oreochromis niloticus）为硬骨鱼类模型，研究了 CXCL12/CXCR4 轴在 IgM+B 细胞中的介导作用。我们的研究结果表明，CXCL12/CXCR4 轴对 IgM+B 细胞具有趋化活性，并促进 IgM+B 细胞的吞噬作用。阻断 CXCR4 严重损害了 IgM+B 细胞的趋化和吞噬作用，减少了病原体感染后 IgM+B 细胞向外周血迁移的百分比和数量。这种迁移减少导致炎症反应减弱，组织细菌负荷增加，存活率降低。我们还发现，进化上保守的 PI3K-AKT 信号通路和 Girdin 参与了链球菌感染期间的免疫反应。PI3K-AKT 信号通路抑制剂可阻止 IgM+B 细胞的趋化和吞噬作用，体外抑制相关蛋白的表达和磷酸化水平，并阻止病原体感染后 IgM+B 细胞向外周血的趋化作用。此外，CXCR4 阻断显著下调了 AKT 和 Girdin 的表达。总之，我们的研究揭示了 CXCL12/CXCR4 轴通过 PI3K-AKT 信号通路在罗非鱼 IgM+B 细胞中的调控机制，表明 CXCL12/CXCR4 轴在 B 细胞中的功能在哺乳动物和硬骨鱼类之间可能是保守的。
