Inactivation of Rab11a GTPase in Macrophages Facilitates Phagocytosis of Apoptotic Neutrophils.
Inactivation of Rab11a GTPase in Macrophages Facilitates Phagocytosis of Apoptotic Neutrophils.
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DOI：
10.4049/jimmunol.1601495
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发表时间：
2017-02-15
期刊：
影响因子：
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通讯作者：
Hu G
中科院分区：
文献类型：
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作者：
Jiang C;Liu Z;Hu R;Bo L;Minshall RD;Malik AB;Hu G
巨噬细胞及时有效地清除凋亡的中性粒细胞(泡沫化)是消退炎症和组织修复所必需的，但其调节机制尚不清楚。在这里，我们研究了小GTP酶Rab11a在调节泡腾作用中的作用，并在此基础上研究了炎性肺损伤的消退。我们观察到，凋亡的中性粒细胞喂养导致骨髓来源的巨噬细胞中Rab11a活性的迅速丧失，并发现与对照细胞相比，siRNA耗尽巨噬细胞中的Rab11a显著增加了对凋亡中性粒细胞的吞噬能力。此外，野生型Rab11a的过表达抑制巨噬细胞的泡腾作用，而显性负性Rab11a(Rab11a S25N)的过表达则增加了中性粒细胞对凋亡的清除。Rab11a基因敲除也增加了巨噬细胞表面CD36的水平，但减少了细胞表面去整合素和金属蛋白酶(ADAM)17的表达。ADAM17的缺失挽救了过度表达野生型Rab11a的巨噬细胞表面CD36表达的下降。此外，阻断CD36可消除在Rab11a耗尽的巨噬细胞中所见的增强的泡沫化作用。在内毒素攻击的小鼠中，气管内滴注Rab11a耗尽的巨噬细胞减少了支气管肺泡灌洗液中的中性粒细胞数量，增加了含有凋亡的中性粒细胞的巨噬细胞数量，并防止了炎性肺损伤。因此，巨噬细胞中的Rab11a因凋亡细胞结合而失活，通过调节ADAM17介导的CD36细胞表面表达来启动对凋亡中性粒细胞的吞噬。我们的结果提出，抑制巨噬细胞中Rab11a的活性可能是激活炎性肺损伤消退的一种有前途的策略。
The timely and efficient clearance of apoptotic neutrophils by macrophages (efferocytosis) is required for the resolution of inflammation and tissue repair, but the regulatory mechanisms remain unclear. Here, we investigated the role of the small GTPase Rab11a in regulating efferocytosis, and on this basis the resolution of inflammatory lung injury. We observed that apoptotic neutrophil feeding induced a rapid loss of Rab11a activity in bone marrow-derived macrophages and found that depletion of Rab11a in macrophages by siRNA dramatically increased the phagocytosis of apoptotic neutrophils compared with control cells. In addition, overexpression of wild type Rab11a inhibited macrophage efferocytosis, whereas overexpression of dominant negative Rab11a (Rab11a S25N) increased the clearance of apoptotic neutrophils. Rab11a knockdown also increased the surface level of CD36 in macrophages, but reduced cell surface expression of a disintegrin and metalloproteinase (ADAM) 17. Depletion of ADAM17 rescued the decreased surface CD36 expression found in macrophages over-expressing wild type Rab11a. Also, blockade of CD36 abolished the augmented efferocytosis seen in Rab11a-depleted macrophages. In mice challenged with endotoxin, intratracheal instillation of Rab11a-depleted macrophages reduced neutrophil count in bronchoalveolar lavage fluid, increased the number of macrophages containing apoptotic neutrophils, and prevented inflammatory lung injury. Thus, Rab11a inactivation in macrophages as result of apoptotic cell binding initiates phagocytosis of apoptotic neutrophils via the modulation of ADAM17-mediated CD36 cell surface expression. Our results raise the possibility that inhibition of Rab11a activity in macrophages is a promising strategy for activating the resolution of inflammatory lung injury.