CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL

Gabor Csanyi, Douglas M. Feck, Pushpankur Ghoshal, Bhupesh Singla, Huiping Lin, Shanmugam Nagarajan, Daniel N. Meijles, Imad Al Ghouleh, Nadiezhda Cantu-Medellin, Eric E. Kelley, Lukasz Mateuszuk, Jeffrey S. Isenberg, Simon Watkins, Patrick J. Pagano

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)886-901
Number of pages16
JournalAntioxidants and Redox Signaling
Volume26
Issue number16
DOIs
StatePublished - Jun 1 2017

Fingerprint

Thrombospondin 1
Fluid dynamics
Macrophages
Foam Cells
CD47 Antigens
Lipids
LDL Lipoproteins
Foams
Actin Depolymerizing Factors
Microfilament Proteins
Proteins
1-Phosphatidylinositol 4-Kinase
Apolipoproteins E
Vascular Diseases
Dendritic Cells
Oxidation-Reduction
Actins
Phosphatidylinositols
oxidized low density lipoprotein
NADPH oxidase 1

Keywords

  • CD47
  • NADPH oxidase
  • macrophages
  • macropinocytosis
  • thrombospondin 1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

Cite this

CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. / Csanyi, Gabor; Feck, Douglas M.; Ghoshal, Pushpankur; Singla, Bhupesh; Lin, Huiping; Nagarajan, Shanmugam; Meijles, Daniel N.; Al Ghouleh, Imad; Cantu-Medellin, Nadiezhda; Kelley, Eric E.; Mateuszuk, Lukasz; Isenberg, Jeffrey S.; Watkins, Simon; Pagano, Patrick J.

In: Antioxidants and Redox Signaling, Vol. 26, No. 16, 01.06.2017, p. 886-901.

Research output: Contribution to journalArticle

Csanyi, G, Feck, DM, Ghoshal, P, Singla, B, Lin, H, Nagarajan, S, Meijles, DN, Al Ghouleh, I, Cantu-Medellin, N, Kelley, EE, Mateuszuk, L, Isenberg, JS, Watkins, S & Pagano, PJ 2017, 'CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL', Antioxidants and Redox Signaling, vol. 26, no. 16, pp. 886-901. https://doi.org/10.1089/ars.2016.6834
Csanyi, Gabor ; Feck, Douglas M. ; Ghoshal, Pushpankur ; Singla, Bhupesh ; Lin, Huiping ; Nagarajan, Shanmugam ; Meijles, Daniel N. ; Al Ghouleh, Imad ; Cantu-Medellin, Nadiezhda ; Kelley, Eric E. ; Mateuszuk, Lukasz ; Isenberg, Jeffrey S. ; Watkins, Simon ; Pagano, Patrick J. / CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. In: Antioxidants and Redox Signaling. 2017 ; Vol. 26, No. 16. pp. 886-901.
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AU - Csanyi, Gabor

AU - Feck, Douglas M.

AU - Ghoshal, Pushpankur

AU - Singla, Bhupesh

AU - Lin, Huiping

AU - Nagarajan, Shanmugam

AU - Meijles, Daniel N.

AU - Al Ghouleh, Imad

AU - Cantu-Medellin, Nadiezhda

AU - Kelley, Eric E.

AU - Mateuszuk, Lukasz

AU - Isenberg, Jeffrey S.

AU - Watkins, Simon

AU - Pagano, Patrick J.

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