Apolipoprotein E Induces Antiinflammatory Phenotype in Macrophages

Abstract

Objectives Apolipoprotein E (apoE) exerts potent anti-inflammatory effects. We here investigated the effect of apoE on the functional phenotype of macrophages. Methods and Results Human apoE receptors VLDL-R or apoER2 were stably expressed in RAW264.7 mouse macrophages. In these cells apoE downregulated markers of the pro-inflammatory M1 phenotype (iNOS, IL-12, MIP-1α), but upregulated markers of the anti-inflammatory M2 phenotype (arginase-I, SOCS3, IL-1RA). In addition, M1 macrophage responses (migration, generation of reactive oxygen species, antibody-dependent cell cytotoxicity, phagocytosis) as well as poly(I:C)- and/or IFN-γ-induced production of pro-inflammatory cytokines, COX-2 expression, and activation of NF-κB, IκB and STAT1 were suppressed in VLDL-R- or apoER2-expressing cells. Conversely, the suppression of M2 phenotype and the enhanced response to poly(I:C) were observed in apoE-producing bone marrow macrophages derived from VLDL-R-deficient mice, but not wild type or LDL receptor-deficient mice. The modulatory effects of apoE on macrophage polarization were inhibited in apoE receptor-expressing RAW264.7 cells exposed to SB220025, a p38MAP kinase inhibitor, and PP1, a tyrosine kinase inhibitor. Accordingly, apoE induced tyrosine kinase-dependent activation of p38MAP kinase in VLDL-R- or apoER2-expressing macrophages. Under in vivo conditions, apoE−/− mice transplanted with apoE-producing wild-type bone marrow showed increased plasma IL-1RA levels and peritoneal macrophages of transplanted animals were shifted to the M2 phenotype (increased IL-1RA production and CD206 expression). Conclusion ApoE signaling via VLDL-R or apoER2 promotes macrophage conversion from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. This effect may represent a novel anti-inflammatory activity of apoE.

Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2

“…Overexpression of VLDLR increased ␤-VLDL-induced lipid accumulation (30). In contrast, it has been shown that treatment of VLDLR-and apoER2-overexpressing macrophages with apoE down-regulated proinflammatory gene and up-regulated anti-inflammatory gene expression in these macrophages (31). Furthermore, a VLDLR deficiency increased intimal thickening after vascular injury and increased necrosis in atherosclerotic lesions (32).…”

Apolipoprotein E polymorphism is associated with both number of diseased vessels and extent of coronary artery disease in Czech patients with CAD

“…This effect can be also mediated by hepatic ApoE, as was proven in mice lacking macrophage-derived ApoE, and is responsible for anti-aterogenic action even without lowering plasma cholesterol levels [9][10][11] . The protein also induce the synthesis of NO in vessel wall 12 and has numerous anti-inflammatory effects 13,14 ApoE is polymorphic, with three isoforms common in general population: E2, E3 and E4. The three isoforms differ in two amino-acids at residues 112 and 158 of the protein.…”

Microenviromental factors controlling macrophage polarization in atherosclerosis

“…These findings indicate that ApoE shifts the balance from a pro-inflammatory to an anti-inflammatory cytokine profile [50].…”