Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon.
Lipid-laden foam macrophages are emerging as key players in early atherogenesis. Even though cytoplasmic lipid bodies (lipid droplets) are now recognized as organelles with cell functions beyond lipid storage, the mechanisms controlling lipid body biogenesis within macrophages and their additional functions in atherosclerosis are not completely elucidated. Here we studied oxLDL-elicited macrophage machinery involved in lipid body biogenesis as well as lipid body roles in leukotriene (LT) synthesis. Both in vivo and in vitro, oxLDL (but not native LDL) induced rapid assembly of cytoplasmic lipid bodies-bearing ADRP within mice macrophages. Such oxLDL-elicited foamy-like phenotype was a pertussis toxin-sensitive process that depended on a paracrine activity of endogenous MCP-1/CCL2 and activation of ERK. Pretreatment with neutralizing anti-MCP-1/CCL2 inhibited macrophage ADRP protein expression induced by oxLDL. By directly immuno-localizing leukotrienes at their sites of synthesis, we showed that oxLDL-induced newly formed lipid bodies function as active sites of LTB(4) and LTC(4) synthesis, since oxLDL-induced lipid bodies within foam macrophages compartmentalized the enzyme 5-lipoxygenase and five lipoxygenase-activating protein (FLAP) as well as newly formed LTB(4) and LTC(4). Consistent with MCP-1/CCL-2 role in ox-LDL-induced lipid body biogenesis, in CCR2 deficient mice both ox-LDL-induced lipid body assembly and LT release were reduced as compared to wild type mice. In conclusion, oxLDL-driven foam cells are enriched with leukotriene-synthesizing lipid bodies--specialized organelles whose biogenic process is mediated by MCP-1/CCL2-triggered CCR2 activation and ERK-dependent downstream signaling--that may amplify inflammatory mediator production in atherosclerosis.
Silva
Adriana R
AR
Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
Pacheco
Patricia
P
Vieira-de-Abreu
Adriana
A
Maya-Monteiro
Clarissa M
CM
D'Alegria
Barbara
B
Magalhães
Kelly G
KG
de Assis
Edson F
EF
Bandeira-Melo
Christianne
C
Castro-Faria-Neto
Hugo C
HC
Bozza
Patricia T
PT
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015289:Leukotrienes / Q000096:biosynthesis*; D008055:Lipids / Q000737:chemistry*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015388:Organelles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000070780:Perilipin-2; D054390:Receptors, CCR2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; C548593:Alox5ap protein, mouse; D002352:Carrier Proteins; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D015289:Leukotrienes; D008055:Lipids; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; C000602982:PLIN2 protein, human; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D054390:Receptors, CCR2; D043562:Receptors, G-Protein-Coupled; C099252:oxidized low density lipoprotein; D001094:Arachidonate 5-Lipoxygenase; D048049:Extracellular Signal-Regulated MAP Kinases