Highlights
- •Low-density-lipoproteins (LDL) accelerate monocyte-macrophage differentiation.
- •LDL upregulate expression of integrins in monocytes.
- •LDL reduce anoikis by affecting the caspase-cascade extrinsic pathway.
- •LDL link lipids, innate immunity and atherosclerosis.
Abstract
Background and aims
High LDL triggers dyslipidemia and atherosclerosis, a chronic inflammatory disease
with participation of the innate immunity system. Monocytes are recruited to areas
of LDL-induced endothelial damage and initiate differentiation. This study was aimed
to investigate the effects of LDL on the early transitional stages of monocyte differentiation
into macrophages.
Methods
Blood monocytes, isolated from healthy donors by their adhesion properties, were exposed
to native-LDL (1.80 mg/mL) for 48-h. Monocyte phenotype was assessed at transcript
and miRNA levels by real-time PCR. Protein-expression was determined by western-blot
and flow-cytometry.
Results
CD14 time-dependently decreased in adhered monocytes, reaching a >4fold decrease at
transcript- and protein-levels after 7-days in culture when cells were already differentiated
into macrophages. At 4-days differentiation, monocytes exposed to LDL reduced CD14-transcrition
>1.5fold in mRNA (p = 0.002) and 34% CD14-protein (p = 0.039), whereas increased in
CD16-expression (p = 0.019). Besides, LDL induced a significant increase in integrin
CD49c (α3-subunit) at mRNA (>2fold, p = 0.008) and protein (>3fold, p = 0.045) level
and a decrease in the apoptosis-effectors CASP8 and CASP3 (p = 0.002 and p = 0.035,
respectively) as well as in the precursor form of the death-receptor DR5 (p = 0.045)
without affecting its mRNA-expression level, suggesting a LDL-dependent post-transcriptional
regulation of DR5. In silico prediction analysis indicated miR-126-3p as a candidate to regulate DR5-expression
and miR-126-3p was shown affected by LDL reaching a significant increase (p = 0.033).
Conclusions
In differentiating human monocytes, LDL stimulates expression of cell-adhesion molecules
and downregulates apoptosis-effectors, regulating anoikis and survival programs in
the early stage macrophages.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: January 05, 2016
Accepted:
January 2,
2016
Received in revised form:
December 22,
2015
Received:
August 13,
2015
Identification
Copyright
© 2016 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
