内化
细胞生物学
CD47型
氮氧化物1
胞饮病
泡沫电池
信号转导
生物
细胞信号
NADPH氧化酶
化学
内吞作用
巨噬细胞
细胞
生物化学
吞噬作用
活性氧
体外
作者
Gábor Csányi,Douglas M. Feck,Pushpankur Ghoshal,Bhupesh Singla,Hui‐Ping Lin,Shanmugam Nagarajan,Daniel N. Meijles,Imad Al Ghouleh,Nadiezhda Cantú‐Medellín,Eric E. Kelley,Łukasz Mateuszuk,Jeffrey S. Isenberg,Simon C. Watkins,Patrick J. Pagano
标识
DOI:10.1089/ars.2016.6834
摘要
Aims: Macropinocytosis has been implicated in cardiovascular and other disorders, yet physiological factors that initiate fluid-phase internalization and the signaling mechanisms involved remain poorly identified. The present study was designed to examine whether matrix protein thrombospondin-1 (TSP1) stimulates macrophage macropinocytosis and, if so, to investigate the potential signaling mechanism involved. Results: TSP1 treatment of human and murine macrophages stimulated membrane ruffle formation and pericellular solute internalization by macropinocytosis. Blockade of TSP1 cognate receptor CD47 and NADPH oxidase 1 (Nox1) signaling, inhibition of phosphoinositide 3-kinase, and transcriptional knockdown of myotubularin-related protein 6 abolished TSP1-induced macropinocytosis. Our results demonstrate that Nox1 signaling leads to dephosphorylation of actin-binding protein cofilin at Ser-3, actin remodeling, and macropinocytotic uptake of unmodified native low-density lipoprotein (nLDL), leading to foam cell formation. Finally, peritoneal chimera studies suggest the role of CD47 in macrophage lipid macropinocytosis in hypercholesterolemic ApoE−/− mice in vivo. Innovation: Activation of a previously unidentified TSP1-CD47 signaling pathway in macrophages stimulates direct receptor-independent internalization of nLDL, leading to significant lipid accumulation and foam cell formation. These findings reveal a new paradigm in which delimited Nox1-mediated redox signaling, independent of classical lipid oxidation, contributes to early propagation of vascular inflammatory disease. Conclusions: The findings of the present study demonstrate a new mechanism of solute uptake with implications for a wide array of cell types, including macrophages, dendritic cells, and cancer cells, and multiple pathological conditions in which matrix proteins are upregulated. Antioxid. Redox Signal. 26, 886–901.
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