Effects of β2/aβ2 on oxLDL-induced CD36 activation in THP-1 macrophages

Life Sci. 2019 Dec 15:239:117000. doi: 10.1016/j.lfs.2019.117000. Epub 2019 Oct 22.

Abstract

Aims: β2-glycoprotein I/anti-β2-glycoprotein I antibody complex (β2/aβ2) could promote oxLDL-induced endothelial inflammation through Toll-like receptor 4 (TLR4), therefore accelerates atherosclerosis in patients with anti-phospholipid syndrome (APS). However, effects of β2/aβ2 and TLR4 on oxLDL-induced CD36 activation in macrophages remain to be elucidated and are currently under investigation.

Materials and methods: THP-1 macrophages with or without the pre-treatment of TAK-242, a TLR4 inhibitor, were treated with RPMI 1640, oxLDL, oxLDL+β2/aβ2 or oxLDL + LPS.CD36 expression and subsequent intracellular lipid accumulation, cholesterol-transportation-related proteins (ACAT1, ABCG1 and ABCA1) expression, inflammatory cytokines (IL-1β, TNF-α and IL-6) secretion, focal adhesion kinases (FAK) activation and matrix metalloproteinases (MMP-2 and MMP-9) expression by these THP-1 macrophages were evaluated. Moreover, effects of TLR4 on oxLDL+β2/aβ2-induced peroxisome proliferators-activated receptor-γ (PPAR-γ) expression and CD36 translocation have also been observed.

Key findings: Compared with oxLDL-treated ones, CD36 expression, intracellular lipid accumulation and FAK activation were inhibited, whereas the levels of inflammatory cytokines and MMPs were upregulated in THP-1 macrophages treated with oxLDL+β2/aβ2 (p < 0.05). Moreover, observed differences between oxLDL-treated and oxLDL+β2/aβ2-treated THP-1 macrophages could be reversed by TAK-242 pre-treatment (p < 0.05). Furthermore, oxLDL+β2/aβ2 promoted PPAR-γ expression and CD36 cytoplasmic translocation in THP-1 macrophages, these effects could also be attenuated by TAK-242 (p < 0.05).

Significance: Through a TLR4 dependent manner, β2/aβ2 inhibited oxLDL-induced CD36 expression, lipid accumulation and FAK activation, while promoted inflammatory cytokines and MMPs expression in THP-1 macrophages, indicating the novel dual roles played by β2/aβ2 in APS-related atherosclerosis.

Keywords: CD36; THP-1 macrophages; TLR4; β2/aβ2.

MeSH terms

  • CD36 Antigens / genetics*
  • Carrier Proteins / metabolism
  • Cell Line
  • Cholesterol / metabolism
  • Cytokines / metabolism
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Lipoproteins, LDL / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Matrix Metalloproteinases / metabolism
  • PPAR gamma / biosynthesis
  • Sulfonamides / pharmacology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • beta 2-Glycoprotein I / antagonists & inhibitors*
  • beta 2-Glycoprotein I / genetics*
  • beta 2-Glycoprotein I / immunology

Substances

  • CD36 Antigens
  • Carrier Proteins
  • Cytokines
  • Lipoproteins, LDL
  • PPAR gamma
  • Sulfonamides
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • beta 2-Glycoprotein I
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
  • oxidized low density lipoprotein
  • Cholesterol
  • Focal Adhesion Kinase 1
  • Matrix Metalloproteinases