Deficiencies of the lipid-signaling enzymes phospholipase D1 and D2 alter cytoskeletal organization, macrophage phagocytosis, and cytokine-stimulated neutrophil recruitment.
Deficiencies of the lipid-signaling enzymes phospholipase D1 and D2 alter cytoskeletal organization, macrophage phagocytosis, and cytokine-stimulated neutrophil recruitment.
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DOI：
10.1371/journal.pone.0055325
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Frohman MA
中科院分区：
文献类型：
--
作者：
Ali WH;Chen Q;Delgiorno KE;Su W;Hall JC;Hongu T;Tian H;Kanaho Y;Di Paolo G;Crawford HC;Frohman MA
细胞迁移和吞噬是由细胞外启动的信号级联引起的，这些信号级联协调了肌动蛋白细胞骨架的动态重组。重组是由局部生成的脂质第二信使招募到活性位点的效应蛋白介导的。磷脂酸（PA）是一种由包括磷脂酶D （PLD）在内的多个酶家族产生的膜磷脂，被认为在这一作用中起作用。在这里，我们发现，从缺乏PLD1或PLD2经典PLD亚型的小鼠制备的巨噬细胞，或PLD活性被药理抑制的野生型巨噬细胞，显示出异构体特异性肌动蛋白细胞骨架异常，这可能是吞噬能力下降的基础。出乎意料的是，在没有任何一种异构体的情况下，甚至当所有PLD活性都被消除时，PA仍然在吞噬体上被检测到。然而，通过成像PA、f -肌动蛋白、f -肌动蛋白网络组织者Rac1和Rac1激活剂DOCK2，可以观察到一个无序的吞噬杯，这表明在吞噬过程中，pld介导的PA产生对整个过程的完整性至关重要。异常的f -肌动蛋白重组还影响了中性粒细胞从脉管系统向间质组织的迁移和外渗。虽然PLD1和PLD2在这些过程中都很重要，但我们也观察到了同工型特异性功能。研究发现，在急性胰腺炎或刺激诱导的皮肤血管化等免疫反应中，pld1驱动的过程在巨噬细胞离开脉管系统的转运中起着关键作用。
Cell migration and phagocytosis ensue from extracellular-initiated signaling cascades that orchestrate dynamic reorganization of the actin cytoskeleton. The reorganization is mediated by effector proteins recruited to the site of activity by locally-generated lipid second messengers. Phosphatidic acid (PA), a membrane phospholipid generated by multiple enzyme families including Phospholipase D (PLD), has been proposed to function in this role. Here, we show that macrophages prepared from mice lacking either of the classical PLD isoforms PLD1 or PLD2, or wild-type macrophages whose PLD activity has been pharmacologically inhibited, display isoform-specific actin cytoskeleton abnormalities that likely underlie decreases observed in phagocytic capacity. Unexpectedly, PA continued to be detected on the phagosome in the absence of either isoform and even when all PLD activity was eliminated. However, a disorganized phagocytic cup was observed as visualized by imaging PA, F-actin, Rac1, an organizer of the F-actin network, and DOCK2, a Rac1 activator, suggesting that PLD-mediated PA production during phagocytosis is specifically critical for the integrity of the process. The abnormal F-actin reorganization additionally impacted neutrophil migration and extravasation from the vasculature into interstitial tissues. Although both PLD1 and PLD2 were important in these processes, we also observed isoform-specific functions. PLD1-driven processes in particular were observed to be critical in transmigration of macrophages exiting the vasculature during immune responses such as those seen in acute pancreatitis or irritant-induced skin vascularization.
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缺乏磷脂酶D1的小鼠中的α（IIB）β（3）整联蛋白活化和剪切依赖性血栓形成。
影响因子：
7.3
作者：
Elvers M;Stegner D;Hagedorn I;Kleinschnitz C;Braun A;Kuijpers ME;Boesl M;Chen Q;Heemskerk JW;Stoll G;Frohman MA;Nieswandt B
通讯作者：
Nieswandt B
影响因子：
3.3
作者：
Du, GW;Huang, P;Frohman, MA
通讯作者：
Frohman, MA
影响因子：
29.4
作者：
Bombardelli, Lorenzo;Carpenter, Eileen S.;Crawford, Howard C.
通讯作者：
Crawford, Howard C.
影响因子：
3.3
作者：
Chae, Young Chan;Kim, Jung Hwan;Ryu, Sung Ho
通讯作者：
Ryu, Sung Ho
影响因子：
4
作者：
Dart, Anna E.;Donnelly, Sara K.;Caron, Emmanuelle
通讯作者：
Caron, Emmanuelle