Cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways mediates macrophage foam cell formation

Abstract

Myeloid differentiation factor 88 (MyD88) and NF-κB play central roles in mediating signal transduction of the Toll-like receptor (TLR) superfamily in human macrophages. The feedback regulation of LDL receptor (LDLR) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) are mediated by the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP)-SREBP2 pathway and are key regulatory elements for cholesterol homeostasis in human cells. This study was designed to investigate cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways in macrophage foam cell formation. phorbol 12-myristate 13-acetate-activated THP-1 macrophages were transfected with negative control or MyD88 small interfering (si)RNA. Transfected cells were incubated with LPS in the absence or presence of LDL or IκB kinase (IKK) inhibitor (BMS-345541). Intracellular cholesterol content was assessed. mRNA and protein expression of LDLR, HMG-CoAR, SCAP, and SREBP2 were examined by real-time RT-PCR and Western blot analysis. Intracellular translocation of SCAP in the organelles was detected by immunofluorecence and confocal microscopy. We demonstrated that LPS-induced cholesterol accumulation was attenuated by applying siRNA against MyD88 in the absence or presence of LDL. LPS increased both gene and protein expression of LDLR and HMG-CoAR by increasing expression and abnormal translocation of SCAP from the endoplasmic reticulum to the Golgi. These effects were blocked by knockdown of MyD88 or blockade of IKK or by knockdown of SCAP, suggesting that the cross-talk between NF-κB and SCAP plays an important role in macrophage foam cell formation and that interfering with the cross-talk might be a potential approach in preventing LPS-induced macrophage foam cell formation.

MicroRNA-33 Regulates the Innate Immune Response via ATP Binding Cassette Transporter-mediated Remodeling of Membrane Microdomains

“…1C). Consistent with past reports (14,15), we also found that the early up-regulation of Srebf-2 is NF-B-dependent as it was attenuated by pretreatment with an NF-B inhibitor (Fig. 1D).…”

TIFA as a crucial mediator for NLRP3 inflammasome

“…Regarding disease onset, EC-specific overexpression of SREBP2(N) in mice induces NLRP3 inflammasome to contribute to atherosclerosis (14). Interestingly, cross-talk between the Toll-like receptor (TLR) 4-MyD88-NF-κB pathway and SREBP2 can facilitate the formation of foam cells from macrophages (15). Collectively, our previous work and that from others suggest that SREBP2 plays a central role in the innate immune response in ECs and macrophages.…”

“…We and others have shown that a variety of stimuli that elicit cellular oxidative stress, such as oxidized phospholipids, angiotensin II, and oxidized LDL (oxLDL), promote the N-terminal cleavage and activation of SREBP2 [i.e., SREBP2(N)] in ECs (14,15). As a result, SREBP2(N) transactivates NLRP3 (14).…”

Inflammatory Stress Induces Statin Resistance by Disrupting 3-Hydroxy-3-Methylglutaryl-CoA Reductase Feedback Regulation

“…We have demonstrated previously that knocking down of MyD88 or using I kappa B kinase inhibitor in a human leukemia cell line-1-derived macrophages attenuates the increase of SCAP and its downstream molecules (nSREBP2 and LDL receptor) by inflammation, suggesting a crosstalk between inflammation and SCAP expression pathway. 32 Overexpression of SCAP in vitro caused statin resistance, whereas knocking down SCAP prevented statin resistance induced by inflammatory stress, suggesting that high expression and abnormal Golgi translocation of SCAP could represent the mechanisms for the statin resistance induced by inflammatory stress.…”