Oxidized LDL/CD36 interaction induces loss of cell polarity and inhibits macrophage locomotion.
Cell polarization is essential for migration and the exploratory function of leukocytes. However, the mechanism by which cells maintain polarity or how cells revert to the immobilized state by gaining cellular symmetry is not clear. Previously we showed that interaction between oxidized low-density lipoprotein (oxLDL) and CD36 inhibits macrophage migration; in the current study we tested the hypothesis that oxLDL/CD36-induced inhibition of migration is the result of intracellular signals that regulate cell polarity. Live cell imaging of macrophages showed that oxLDL actuated retraction of macrophage front end lamellipodia and induced loss of cell polarity. Cd36 null and macrophages null for Vav, a guanine nucleotide exchange factor (GEF), did not show this effect. These findings were caused by Rac-mediated inhibition of nonmuscle myosin II, a cell polarity determinant. OxLDL induced dephosphorylation of myosin regulatory light chain (MRLC) by increasing the activity of Rac. Six-thioguanine triphosphate (6-thio-GTP), which inhibits Vav-mediated activation of Rac, abrogated the effect of oxLDL. Activation of the Vav-Rac-myosin II pathway by oxidant stress may induce trapping of macrophages at sites of chronic inflammation such as atherosclerotic plaque.
Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Young Mi
YM
Park
Judith A
JA
Drazba
Amit
A
Vasanji
Thomas
T
Egelhoff
Maria
M
Febbraio
Roy L
RL
Silverstein
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D002465:Cell Movement; D016764:Cell Polarity; D002522:Chlorocebus aethiops; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D011554:Pseudopodia / Q000378:metabolism / Q000502:physiology; D013873:Thionucleotides / Q000494:pharmacology; D059008:Time-Lapse Imaging; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D001381:Azepines; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D018994:Myosin Light Chains; D009281:Naphthalenes; D051567:Proto-Oncogene Proteins c-vav; D013873:Thionucleotides; C496619:Vav1 protein, mouse; C099252:oxidized low density lipoprotein; C070571:ML 7; C032827:6-thioguanosine 5'-triphosphate; D006160:Guanosine Triphosphate; D009219:Myosin-Light-Chain Kinase; D020744:rac GTP-Binding Proteins