TY - JOUR
T1 - CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL
AU - Csányi, Gábor
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.
N1 - Publisher Copyright:
© Mary Ann Liebert, Inc.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - CD47
KW - NADPH oxidase
KW - macrophages
KW - macropinocytosis
KW - thrombospondin 1
UR - http://www.scopus.com/inward/record.url?scp=85019346747&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019346747&partnerID=8YFLogxK
U2 - 10.1089/ars.2016.6834
DO - 10.1089/ars.2016.6834
M3 - Article
C2 - 27958762
AN - SCOPUS:85019346747
SN - 1523-0864
VL - 26
SP - 886
EP - 901
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 16
ER -