Sphingolipid-mediated Inhibition of Apoptotic Cell Clearance by Alveolar Macrophages
Sphingolipid-mediated Inhibition of Apoptotic Cell Clearance by Alveolar Macrophages
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DOI：
10.1074/jbc.m110.137604
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发表时间：
2010-12-17
影响因子：
4.8
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
--
作者：
Petrusca, Daniela N.;Gu, Yuan;Petrache, Irina
肺泡巨噬细胞（AM）对凋亡细胞（巨噬细胞增多症）的清除减少可能导致肺气肿的炎症。吸烟（CS）引起的神经酰胺上调与AM蓄积和肺实质中凋亡肺泡上皮细胞和内皮细胞检测增加有关。我们假设神经酰胺抑制凋亡细胞的AM吞噬。释放内源性神经酰胺通过鞘磷脂酶或外源性神经酰胺治疗剂量依赖性受损的凋亡Jurkat细胞吞噬原代大鼠或人AM，无论神经酰胺的分子种类。同样，在体内增加肺神经酰胺通过intrichelheal滴注在大鼠中显着降低了灌注的目标凋亡胸腺细胞的吞噬居民AM。神经酰胺诱导的神经鞘氨醇减少的机制依赖于神经酰胺酶产生鞘氨醇。鞘氨醇处理概括了神经酰胺的作用，剂量依赖性地抑制凋亡细胞清除。神经酰胺对细胞外红细胞作用的影响与减少膜皱褶形成和减弱Rac 1质膜募集有关。组成性活性Rac1过表达挽救了AM胞浆细胞增多症对神经酰胺的影响。CS暴露显着增加AM神经酰胺和概括神经酰胺对Rac 1膜招聘的鞘氨醇依赖性的方式。重要的是，CS通过神经酰胺依赖性鞘氨醇的产生而显著抑制AM胞浆细胞的生成。这些结果表明，过量的肺神经酰胺可能通过引起结构细胞的凋亡和AM对其清除的抑制来放大肺气肿中的肺损伤。
A decreased clearance of apoptotic cells (efferocytosis) by alveolar macrophages (AM) may contribute to inflammation in emphysema. The up-regulation of ceramides in response to cigarette smoking (CS) has been linked to AM accumulation and increased detection of apoptotic alveolar epithelial and endothelial cells in lung parenchyma. We hypothesized that ceramides inhibit the AM phagocytosis of apoptotic cells. Release of endogenous ceramides via sphingomyelinase or exogenous ceramide treatments dose-dependently impaired apoptotic Jurkat cell phagocytosis by primary rat or human AM, irrespective of the molecular species of ceramide. Similarly, in vivo augmentation of lung ceramides via intratracheal instillation in rats significantly decreased the engulfment of instilled target apoptotic thymocytes by resident AM. The mechanism of ceramide-induced efferocytosis impairment was dependent on generation of sphingosine via ceramidase. Sphingosine treatment recapitulated the effects of ceramide, dose-dependently inhibiting apoptotic cell clearance. The effect of ceramide on efferocytosis was associated with decreased membrane ruffle formation and attenuated Rac1 plasma membrane recruitment. Constitutively active Rac1 overexpression rescued AM efferocytosis against the effects of ceramide. CS exposure significantly increased AM ceramides and recapitulated the effect of ceramides on Rac1 membrane recruitment in a sphingosine-dependent manner. Importantly, CS profoundly inhibited AM efferocytosis via ceramide-dependent sphingosine production. These results suggest that excessive lung ceramides may amplify lung injury in emphysema by causing both apoptosis of structural cells and inhibition of their clearance by AM.