Apolipoprotein E inhibits Toll-like receptor (TLR)-3- and TLR-4-mediated macrophage activation through distinct mechanisms

Abstract

Synopsis Previous studies showed that apolipoprotein E (apoE) expression in macrophages suppresses inflammatory response. Whether the endogenously synthesized apoE acts intracellularly or after its secretion in suppressing macrophage inflammation remains unclear. The current study used the murine macrophage cell line RAW 264.7 to examine the influence of exogenous apoE on macrophage inflammatory responses induced by toll-like receptor (TLR)-4 and TLR-3 agonists lipopolysaccharide (LPS) and poly(I-C), respectively. Results showed that exogenously added apoE suppressed LPS- and poly(I-C)-induction of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α secretion by RAW 264.7 cells. The mechanism was related to apoE suppression of TLR agonist-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun. A peptide containing tandem repeat sequence of the receptor binding domain of apoE, apoE(141–155)2, was similarly effective in inhibiting LPS- and poly(I-C)-induced macrophage inflammatory response. Reductive methylation of lysine residues in apoE, which abolished its receptor binding capability without affecting its ability to interact with heparin-sulfate proteoglycans (HSPG), inhibited the ability of apoE to suppress macrophage response to LPS but had no effect on apoE suppression of poly(I-C)-induced macrophage activation. The ability of apoE to suppress poly(I-C)-induced pro-inflammatory cytokine production was abolished by heparinase treatment of RAW 264.7 cells to remove cell surface HSPG. Taken together, these results indicate that exogenous apoE inhibits macrophage inflammatory response to TLR4- and TLR-3 agonists through distinct mechanisms related to receptor and HSPG binding, respectively, and that these inhibitory effects converged on suppression of JNK and c-Jun activation that are necessary for macrophage activation.

Selective suppression of adipose tissue apoE expression impacts systemic metabolic phenotype and adipose tissue inflammation

“…It should be noted that the difference in infl ammatory phenotype we have measured in adipose tissue from control and SEKO mice may be related to the reduced apoE expression in either macrophages or adipocytes. Others have shown that exogenously added apoE can modulate macrophage infl ammatory state but, interestingly, suppresses the infl ammatory phenotype ( 37,38 ). Our results, however, imply that the expression of apoE in adipose tissue promotes an infl ammatory phenotype.…”

Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress

“…Previous studies have shown that apoE3 may protect against metabolic diseases via its anti-oxidation and anti-inflammatory properties (2,6), including its attenuation of toll-like receptor signaling and converting the pro-inflammatory M1 macrophages to the anti-inflammatory M2 macrophage phenotype (7,8). In the vessel wall, apoE3 also induces anti-inflammatory signaling events that limit injury-induced neointimal hyperplasia and hypercholesterolemia-induced atherosclerosis (9 -13).…”

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

“…For example, apoE produced by macrophages relieves the inhibition of eNOS by caveolin in endothelial cells by displacing the caveolin from its complex with the NO synthase (87). Exogenous apoE inhibits macrophage activation by TLR3 and TLR4 agonists through distinct mechanisms (88). There is also an effect of apoE on arterial smooth muscle cells that is most clearly demonstrated in the increased formation of neointimal expansion in Apoe / mice in response to endothelial denudation (89).…”