CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL.
Antioxid Redox Signal
; 26(16): 886-901, 2017 06 01.
Article
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| MEDLINE
| ID: mdl-27958762
ABSTRACT
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.Palavras-chave
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MEDLINE
Assunto principal:
Fatores de Despolimerização de Actina
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
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Antígeno CD47
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NADPH Oxidase 1
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Hipercolesterolemia
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Macrófagos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article