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

Gábor Csányi, 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

13 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

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

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    Csányi, G., Feck, D. M., Ghoshal, P., Singla, B., Lin, H., Nagarajan, S., Meijles, D. N., Al Ghouleh, I., Cantu-Medellin, N., Kelley, E. E., Mateuszuk, L., Isenberg, J. S., Watkins, S., & Pagano, P. J. (2017). CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL. Antioxidants and Redox Signaling, 26(16), 886-901. https://doi.org/10.1089/ars.2016.6834