Involvement of TLR4 in Oxidized LDL/β2GPI/Anti-β2GPI-Induced Transformation of Macrophages to Foam Cells

Zhang, Xiaolei; Xie, Yingping; Zhou, Hong; Xu, Ya; Liu, Jingjing; Xie, Hong; Yan, Jinchuan

doi:10.5551/jat.24372

Cited by 39 publications

(38 citation statements)

References 49 publications

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“…Recent studies have suggested that EGFR can also be activated without the typical ligands29, and it can function in intracellular membranes30. Toll-like receptor 4 (TLR4) has been reported to be directly activated by ox-LDL and mediate pathological pathways and phenotypes313233. In addition, expression of TLR4-induced genes in lipopolysaccharide-stimulated myeloid cells requires EGFR kinase activity18.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Wang

Huang

et al. 2017

Sci Rep

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Atherosclerosis is a progressive disease leading to loss of vascular homeostasis and entails fibrosis, macrophage foam cell formation, and smooth muscle cell proliferation. Recent studies have reported that epidermal growth factor receptor (EGFR) is involved vascular pathophysiology and in the regulation of oxidative stress in macrophages. Although, oxidative stress and inflammation play a critical role in the development of atherosclerosis, the underlying mechanisms are complex and not completely understood. In the present study, we have elucidated the role of EGFR in high-fat diet-induced atherosclerosis in apolipoprotein E null mice. We show increased EGFR phosphorylation and activity in atherosclerotic lesion development. EGFR inhibition prevented oxidative stress, macrophage infiltration, induction of pro-inflammatory cytokines, and SMC proliferation within the lesions. We further show that EGFR is activated through toll-like receptor 4. Disruption of toll-like receptor 4 or the EGFR pathway led to reduced inflammatory activity and foam cell formation. These studies provide evidence that EGFR plays a key role on the pathogenesis of atherosclerosis, and suggests that EGFR may be a potential therapeutic target in the prevention of atherosclerosis development.

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Section: Resultsmentioning

confidence: 99%

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Wang

Huang

et al. 2017

Sci Rep

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“…The main role of the aβ2GPI antibodies, especially those specifically targeting domain I [20], is widely accepted and present results seem to further confirm their importance with regard to CV risk stratification, since PAF-AH appeared particularly elevated in aβ2GPI-positive patients and more so in those displaying LAC activity and carrying the IgG isotype. This particular association may be explained by the fact that IgG aβ2GPI antibodies are able to recognize the stable complex between oxLDL and β2GPI, thus facilitating macrophage-derived foam cell formation in patients with APS [15]. The immune-pathological mechanisms sustained by oxLDL/β2GPI complexes are not yet fully understood, but Toll-like receptor 4 (TLR4) was recently shown to be involved [15].…”

Section: Discussionmentioning

confidence: 99%

“…This particular association may be explained by the fact that IgG aβ2GPI antibodies are able to recognize the stable complex between oxLDL and β2GPI, thus facilitating macrophage-derived foam cell formation in patients with APS [15]. The immune-pathological mechanisms sustained by oxLDL/β2GPI complexes are not yet fully understood, but Toll-like receptor 4 (TLR4) was recently shown to be involved [15]. TLR4 could be the key player linking PAF-AH up-regulation to aβ2GPI IgG antibodies in APS, as evidenced by a mouse model of preterm delivery which demonstrated that PAF effects and signalling depend upon TLR4 stimulation [21].…”

Section: Discussionmentioning

confidence: 99%

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Exploring the plasmatic platelet-activating factor acetylhydrolase activity in patients with anti-phospholipid antibodies

Fabris

Cifù

Pistis

et al. 2017

Autoimmun Highlights

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PurposeTo explore the role of plasmatic platelet-activating factor acetylhydrolase (PAF-AH), a marker of cardiovascular risk, in patients with anti-phospholipid antibodies (aPL).MethodsPAF-AH activity was assessed in a series of 167 unselected patients screened for aPL in a context of thrombotic events, risk of thrombosis or obstetric complications and in 77 blood donors.Results116/167 patients showed positive results for at least one aPL among IgG/IgM anti-prothrombin/phosphatidylserine (aPS/PT), anti-cardiolipin (aCL), anti-beta2-glycoprotein I (aβ2GPI) or lupus anticoagulant (LAC), while 51/167 patients resulted aPL-negative. LAC+ patients disclosed higher PAF-AH than LAC-negative (22.1 ± 6.4 nmol/min/ml vs. 19.5 ± 4.1 nmol/min/ml; p = 0.0032), and aPL-negative patients (p = 0.03). Patients presenting positive IgG aβ2GPI disclosed higher PAF-AH than patients with only IgM aβ2GPI-positive antibodies (23.1 ± 7.2 nmol/min/ml vs. 20.1 ± 5.3 nmol/min/ml; p = 0.035), as well as than patients showing only isolated LAC, aCL or aPS/PT (16.9 ± 3.8 nmol/min/ml; p = 0.003).ConclusionsPAF-AH plasmatic activity is particularly up-regulated in LAC+ and in aβ2GPI IgG+ patients, possibly representing an alternative prognostic biomarker for the therapeutic management of APS patients.

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“…Therefore, the IRAK1/4 inhibitor reduced the production of IL-1 and TNF-while also decreasing TLR4 expression and NF B activation. Furthermore, the expression of TLR4 and activation of NF-B played an important role during the transformation of macrophages to foam cells, which may accelerate the development of atherosclerosis 35) . TLR4 signaling was the mediator of chronic inflammation and an important regulator of atherogenesis 36) .…”

Section: Acknowledgmentsmentioning

confidence: 99%

Interleukin-1 Receptor-Associated Kinase 1/4 as a Novel Target for Inhibiting Neointimal Formation After Carotid Balloon Injury

Bai

Zhou

et al. 2015

JAT

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Aim:Interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 play essential roles in the induction of inflammatory gene products. We aimed to investigate the effect of the inhibition of IRAK1 and IRAK4 kinase activities on neointimal formation in rats with carotid artery balloon injuries using the IRAK1/4 inhibitor N-(2-Morpholinylethyl)-2-(3-nitrobenzoylamido)-benzimidazole, a cell-permeable benzimidazole compound. Methods: Wistar rats and vascular smooth muscle cells (VSMCs) isolated from the thoracic aortas were used. Toll-like receptor 4 (TLR4)-mediated nuclear factor kappa B (NF B) signaling pathway was revealed by microarrays analysis. In addition, the differential expression of the TLR4 pathway genes, including TLR4, IRAK1, I B , and interleukin-1 (IL-1 ), was confirmed by quantitative real-time polymerase chain reaction. Immunohistochemical staining, elastic-van Gieson and Masson staining, 5-ethynyl-2´-deoxyuridine staining, enzyme-linked immunosorbent assay, transwell migration assay and western blotting were also contributed for relevant detection. Results:The expression of TLR4 protein gradually increased at days 1, 3, 7, and 21 after balloon injury compared with the uninjured group. The dual inhibition of IRAK1 and IRAK4 attenuated neointimal formation and fibrotic remodeling after injury in vivo and suppressed VSMC proliferation and migration in vitro. The production of mediators such as tumor necrosis factor-and IL-1 in injured arteries were also reduced by the inhibition of IRAK1 and IRAK4. The expression of NF B p65-and F4/80-positive cells in inhibitor rats were fewer than those in control rats at day 7, while IRAK1 expression was markedly higher at day 3 in inhibitor rats. Furthermore, western blotting analysis revealed that the IRAK1/4 inhibitor suppressed the IRAK1 and IRAK4 kinase activities and the activation of the TLR4-mediated NF B pathway in vivo and in vitro. Conclusions: This study suggested that IRAK1/4 could serve as a potential therapeutic target to suppress neointimal formation in carotid arteries after balloon injury through the TLR4/NF B signaling pathway. IntroductionRestenosis is a healing response of the arterial wall to mechanical injury after percutaneous coronary intervention (PCI). Vascular smooth muscle cell (VSMC) proliferation and migration are critical to 1318 tion of IRAK1 and IRAK4 kinase activities would be predicted to leave some degree of host defense intact while still reducing inflammatory responses 18) . A novel cell-permeable benzimidazole compound can act as a potent and selective inhibitor of IRAK1 and IRAK4 and has been tested in plasmacytoid dendritic cells from systemic lupus erythematosus and rheumatoid arthritis patients 19) , human primary small airway epithelial cells in chronic obstructive pulmonary disease 20) , and rat brain hypoxia/ischemiainduced neuronal injury 21) ; however, it has not yet been employed in vascular research. To the best of our knowledge, there are no published studies on the role of IRAK1 and IRAK4 kinase activities in...

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Involvement of TLR4 in Oxidized LDL/β2GPI/Anti-β2GPI-Induced Transformation of Macrophages to Foam Cells

Cited by 39 publications

References 49 publications

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Exploring the plasmatic platelet-activating factor acetylhydrolase activity in patients with anti-phospholipid antibodies

Interleukin-1 Receptor-Associated Kinase 1/4 as a Novel Target for Inhibiting Neointimal Formation After Carotid Balloon Injury

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