The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

Hovland, Anders; Jonasson, Lena; Garred, Peter; Yndestad, Arne; Aukrust, Pål; Lappegård, Knut Tore; Espevik, Terje; Mollnes, Tom Eirik

doi:10.1016/j.atherosclerosis.2015.05.038

Cited by 92 publications

(64 citation statements)

References 200 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…NF-κB can also be regulated under ox-LDL stimulation. As formerly reported, ox-LDL might upregulate IL-6 via increasing NF-kB in an IGF2-dependent way in THP-1 macrophages [24], ox-LDL stimulation can activate the TLR4/MyD88/NF-kB inflammatory signaling pathway in vascular smooth muscle cell and finally promotes the formation of foam cell [25], and in peripheral blood mononuclear cells extracted from unstable angina patients, ox-LDL may induced the activation of NF-kB [8]. PTPRO has been shown to influence the activation of transcription factors NF-κB, which mediates classical inflammatory signaling pathways in various diseases.…”

Section: Discussionmentioning

confidence: 72%

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

Liang

Wang

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Critical roles of phosphatase receptor type O (PTPRO) and toll-like receptor 4 (TLR4) have been implicated in inflammation. However, little is known about their functional effects on atherosclerosis (AS). We aim to study their potential function in AS. Methods: An oxidized low-density lipoprotein (ox-LDL) induced AS model constructed with PTPRO over-expressing RAW264.7 cells and PTPRO knockout macrophages. Cell apoptosis was assayed by flow cytometry and fatty accumulation was evaluated by oil red staining. The production of ROS (reactive oxygen species), SOD (superoxide dismutase), MDA (malondialdehyde), TC (Triglyceride), and TG (total cholesterol) was evaluated. Western blot was performed to detect the expression of CD36, TLR4 and nuclear factor kB (NF-κB). Results: PTPRO expression was promoted in a dose-dependent and time-dependent manner following ox-LDL challenging. In PTPRO-over-expressing cells, CD36 expression and the level of oil-red staining, TC and TG were increased; ROS production, MDA and level of cell apoptosis were improved, but SOD was reduced. However, in PTPRO knockout cells opposite results were found. TLR4 and NF-κB/p65 phosphorylation was significantly enhanced in PTPRO over-expressing cells, while significantly down-regulated in PTPRO knockout cells. Conclusion: PTPRO plays ital roles in AS via promoting ox-LDL induced oxidative stress and cell apoptosis through TLR4/NF-κB pathway.

show abstract

Section: Discussionmentioning

confidence: 72%

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

Liang

Wang

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…We identified TLR4 as a potential activator of EGFR in macrophages. TLR has been shown to be important in activated macrophages, regulating nucleotide-binding domain and leucine-rich repeat containing (NLR) family, pyrin domain containing 3 (NLRP3) inflammasomes15545556. We showed phosphorylation of EGFR/AKT/ERK to be deficient in macrophages derived from TLR4 −/− mice.…”

Section: Discussionmentioning

confidence: 81%

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

Wang

Huang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

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.

show abstract

“…Whereas an age-related contribution has, for example, been reported in atherosclerosis [102], there is a particular interest in Alzheimer’s disease (AD) and other neurodegenerative/neurological diseases [90]. Animal models support the two-edged effect of complement in AD, in which C1q-mediated triggering of the CP and subsequent generation of terminal pathway effectors fuel an inflammatory milieu that contribute to disease progression.…”

Section: New Frontiers: Rare Re-emerging and Unexpected Indicationsmentioning

confidence: 99%

New milestones ahead in complement-targeted therapy

Ricklin

Lambris

2016

Seminars in Immunology

125

View full text Add to dashboard Cite

The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.

show abstract

The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis

Cited by 92 publications

References 200 publications

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

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

New milestones ahead in complement-targeted therapy

Contact Info

Product

Resources

About