Arf6 regulates energy metabolism in neutrophils
Arf6 regulates energy metabolism in neutrophils
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DOI：
10.1016/j.freeradbiomed.2021.07.001
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发表时间：
2021-07-09
影响因子：
7.4
通讯作者：
Bourgoin, Sylvain G.
中科院分区：
文献类型：
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作者：
Gamara, Jouda;Davis, Lynn;Bourgoin, Sylvain G.
小的GTd 6 Arf 6调节许多细胞过程，包括细胞骨架重塑、受体内吞作用和病原体吞噬作用。已知中性粒细胞（PMN）样细胞中的Arf 6沉默抑制趋化肽介导的磷脂酶D活化、氧化爆发和β 2整联蛋白依赖性粘附。在条件性基因敲除（cKO）小鼠中，Arf 6缺陷型PMN向炎症部位的迁移减少，并与β 2整合素的细胞表面表达减少相关。在这项研究中，我们评估了Arf 6缺失对小鼠气囊中分离的PMN的功能和基因表达谱的影响。参与对氧水平、红细胞和骨髓分化、巨噬细胞趋化性、对化学物质的反应、细胞凋亡、RNA不稳定、内体组织和囊泡转运的许多基因在Arf 6的PMN cKO中差异表达。Lpar 6和Lacc-1分别是上调和下调最多的基因。Arf 6的缺失也降低了中性粒细胞中Lacc-1的蛋白水平，并且THP-1单核细胞中Arf 6的沉默延迟了LPS介导的Lacc-1表达。我们报告，fMLP或酵母多糖诱导的糖酵解和耗氧率都降低了空气袋中性粒细胞，但在骨髓中性粒细胞的Arf 6 cKO小鼠。氧消耗减少与超氧化物和ROS产生减少相关。中性粒细胞中Arf 6的缺失也降低了吞噬作用并干扰了细胞凋亡。这些数据表明，Arf 6调节能量代谢，这可能有助于PMN-Arf 6 cKO中吞噬功能受损、ROS产生和细胞凋亡。本研究为Arf 6在中性粒细胞中的功能和炎症通路的影响提供了新的信息。
The small GTPase Arf6 regulates many cellular processes, including cytoskeletal remodeling, receptor endocytosis, and pathogen phagocytosis. Arf6 silencing in neutrophil (PMN)-like cells is well-known to inhibit chemotactic peptide-mediated activation of phospholipase D, the oxidative burst, and beta 2 integrin-dependent adhesion. In conditional knockout (cKO) mice, the migration to inflammatory sites of Arf6-deficient PMNs was diminished and associated with reduced cell surface expression of beta 2 integrins. In this study we assessed the impact of Arf6 depletion on the functions and gene expression profile of PMNs isolated from the mouse air pouch. Numerous genes involved in response to oxygen levels, erythrocyte and myeloid differentiation, macrophage chemotaxis, response to chemicals, apoptosis, RNA destabilization, endosome organization, and vesicle transport were differentially expressed in PMNs cKO for Arf6. Lpar6 and Lacc-1 were the most up-regulated and downregulated genes, respectively. The deletion of Arf6 also decreased Lacc-1 protein level in PMNs, and silencing of Arf6 in THP-1 monocytic cells delayed LPS-mediated Lacc-1 expression. We report that fMLP or zymosaninduced glycolysis and oxygen consumption rate were both decreased in air pouch PMNs but not in bone marrow PMNs of Arf6 cKO mice. Reduced oxygen consumption correlated with a decrease in superoxide and ROS production. Deletion of Arf6 in PMNs also reduced phagocytosis and interfered with apoptosis. The data suggest that Arf6 regulates energy metabolism, which may contribute to impaired phagocytosis, ROS production, and apoptosis in PMN-Arf6 cKO. This study provides new information on the functions and the inflammatory pathways influenced by Arf6 in PMNs.