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Singh A, Maurya VP, Dewangan R, Singh M, Srivastava AK, Kumar A. Associations between Toll-like receptor 4 Asp299Gly polymorphism and susceptibility to intracranial aneurysm among male and female patients within the North Indian population. Neurol Res 2025; 47:51-62. [PMID: 39658332 DOI: 10.1080/01616412.2024.2438617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 12/01/2024] [Indexed: 12/12/2024]
Abstract
OBJECTIVES Intracranial aneurysms (IA), often remain asymptomatic until they get ruptured, invariably leads to subarachnoid hemorrhage (SAH), and is influenced by both genetic and environmental factors. Recent studies indicated inflammation as a key player in IA development. This study delves into genetic variations within inflammatory pathways, focusing on TLR4-mediated cytokine release as potential IA biomarkers. METHODS Eighty IA patients and eighty healthy controls from North India participated, and demographic and clinical data were analyzed, including gender-stratified comparisons of TLR4 Asp299Gly genotype and TLR4 expression. Histological and molecular analyses of blood and brain tissue were done using SEM imaging, qPCR, and western blot. RESULTS Our result revealed elevated TLR4 expression in IA patients, with SEM imaging indicating intracerebral damage. TLR4 Asp299Gly heterozygote genotype was less prevalent in IA patients, suggesting a protective effect against IA development. Moreover, TNF-α levels were significantly higher in IA patients, indicating an inflammatory response. Further, TNF-α expression was downregulated in heterozygous patients, suggesting TLR4 Asp299Gly gene polymorphism affects the activation of TNF-α expression. Gender-based analysis between control and aneurysm cases showed a decrease in TLR4 Asp299Gly heterozygote genotype with heightened TLR4 expression and neurological deficits in IA female patients compared to males. CONCLUSIONS This study highlights the association between TLR4 Asp299Gly genotype and IA susceptibility in North Indian populations, linking increased TLR4 expression to IA pathogenesis. Gender-specific disparities in TLR4 genotype and expression underscore the need for personalized treatment strategies, with TLR4 signaling modulation emerging as a promising therapeutic avenue warranting further investigation.
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Affiliation(s)
- Anjali Singh
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Ved Prakash Maurya
- Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Ritu Dewangan
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Mayank Singh
- Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Arun Kumar Srivastava
- Department of Neurosurgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Alok Kumar
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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2
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Carnt NA, Pang I, Burdon KP, Calder V, Dart JK, Subedi D, Hardcastle AJ. Innate and Adaptive Gene Single Nucleotide Polymorphisms Associated With Susceptibility of Severe Inflammatory Complications in Acanthamoeba Keratitis. Invest Ophthalmol Vis Sci 2021; 62:33. [PMID: 33755043 PMCID: PMC7991962 DOI: 10.1167/iovs.62.3.33] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Purpose Over a third of patients with Acanthamoeba keratitis (AK) experience severe inflammatory complications (SICs). This study aimed to determine if some contact lens (CL) wearers with AK were predisposed to SICs due to variations in key immune genes. Methods CL wearers with AK who attended Moorfields Eye Hospital were recruited prospectively between April 2013 and October 2014. SICs were defined as scleritis and/or stromal ring infiltrate. Genomic DNA was processed with an Illumina Low Input Custom Amplicon assay of 58 single nucleotide polymorphism (SNP) targets across 18 genes and tested for association in PLINK. Results Genomic DNA was obtained and analyzed for 105 cases of AK, 40 (38%) of whom experienced SICs. SNPs in the CXCL8 gene encoding IL-8 was significantly associated with protection from SICs (chr4: rs1126647, odds ratio [OR] = 0.3, P = 0.005, rs2227543, OR = 0.4, P = 0.007, and rs2227307, OR = 0.4, P = 0.02) after adjusting for age, sex, steroids prediagnosis, and herpes simplex keratitis (HSK) misdiagnosis. Two TLR-4 SNPs were associated with increased risk of SICs (chr9: rs4986791 and rs4986790, both OR = 6.9, P = 0.01). Th-17 associated SNPs (chr1: IL-23R rs11209026, chr2: IL-1β rs16944, and chr12: IL-22 rs1179251) were also associated with SICs. Conclusions The current study identifies biologically relevant genetic variants in patients with AK with SICs; IL-8 is associated with a strong neutrophil response in the cornea in AK, TLR-4 is important in early AK disease, and Th-17 genes are associated with adaptive immune responses to AK in animal models. Genetic screening of patients with AK to predict severity is viable and this would be expected to assist disease management.
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Affiliation(s)
- Nicole A Carnt
- School of Optometry and Vision Science, University of New South Wales (UNSW), Sydney, Australia.,Westmead Institute for Medical Research, Westmead, New South Wales, Australia.,University College London (UCL) Institute of Ophthalmology, London, United Kingdom
| | - Ignatius Pang
- School of Biotechnology and Biomolecular Sciences, University of New South Wales (UNSW), Sydney, Australia
| | - Kathryn P Burdon
- Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | - Virginia Calder
- University College London (UCL) Institute of Ophthalmology, London, United Kingdom
| | - John K Dart
- University College London (UCL) Institute of Ophthalmology, London, United Kingdom.,Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
| | - Dinesh Subedi
- School of Optometry and Vision Science, University of New South Wales (UNSW), Sydney, Australia.,School of Biological Sciences, Monash University, Clayton, Australia
| | - Alison J Hardcastle
- University College London (UCL) Institute of Ophthalmology, London, United Kingdom
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Macrophage Long Non-Coding RNAs in Pathogenesis of Cardiovascular Disease. Noncoding RNA 2020; 6:ncrna6030028. [PMID: 32664594 PMCID: PMC7549353 DOI: 10.3390/ncrna6030028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/21/2022] Open
Abstract
Chronic inflammation is inextricably linked to cardiovascular disease (CVD). Macrophages themselves play important roles in atherosclerosis, as well as acute and chronic heart failure. Although the role of macrophages in CVD pathophysiology is well-recognized, little is known regarding the precise mechanisms influencing their function in these contexts. Long non-coding RNAs (lncRNAs) have emerged as significant regulators of macrophage function; as such, there is rising interest in understanding how these nucleic acids influence macrophage signaling, cell fate decisions, and activity in health and disease. In this review, we summarize current knowledge regarding lncRNAs in directing various aspects of macrophage function in CVD. These include foam cell formation, Toll-like receptor (TLR) and NF-kβ signaling, and macrophage phenotype switching. This review will provide a comprehensive understanding concerning previous, ongoing, and future studies of lncRNAs in macrophage functions and their importance in CVD.
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4
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Rienks M, Papageorgiou A, Wouters K, Verhesen W, Leeuwen RV, Carai P, Summer G, Westermann D, Heymans S. A novel 72-kDa leukocyte-derived osteoglycin enhances the activation of toll-like receptor 4 and exacerbates cardiac inflammation during viral myocarditis. Cell Mol Life Sci 2016; 74:1511-1525. [PMID: 27878326 PMCID: PMC5357299 DOI: 10.1007/s00018-016-2423-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Revised: 10/20/2016] [Accepted: 11/14/2016] [Indexed: 01/04/2023]
Abstract
Background Viral myocarditis can severely damage the myocardium through excessive infiltration of immune cells. Osteoglycin (OGN) is part of the small leucine-rich repeat proteoglycan (SLRP) family. SLRP’s may affect inflammatory and fibrotic processes, but the implication of OGN in cardiac inflammation and the resulting injury upon viral myocarditis is unknown. Methods and results This study uncovered a previously unidentified 72-kDa variant of OGN that is predominant in cardiac human and mouse samples of viral myocarditis. Its absence in mice significantly decreased cardiac inflammation and injury in Coxsackievirus-B3-induced myocarditis. It also delayed mortality in lipopolysaccharide-induced endotoxemia going along with a reduced systemic production of pro-inflammatory cytokines. This 72-kDa OGN is expressed in the cell membrane of circulating and resident cardiac macrophages and neutrophils. Co-immunoprecipitation and OGN siRNA experiments revealed that this 72-kDa variant activates the toll-like receptor-4 (TLR4) with a concomitant increase in IL-6, TNF-α, IL-1β, and IL-12 expression. This immune cell activation by OGN occurred via MyD88 and increased phosphorylation of c-jun. Finally, the 72-kDa chondroitin sulfate is the result of O-linked glycosylation of the 32-kDa protein core of OGN. In contrast, the 34-kDa dermatan sulfate-OGN, involved in collagen cross linking, was also the result of O-linked glycosylation. Conclusion The current study discovered a novel 72-kDa chondroitin sulfate-OGN that is specific for innate immune cells. This variant is able to bind and activate TLR4. The absence of OGN decreases cytokine production by both circulating and cardiac leukocytes upon (systemic) LPS exposure, and reduces cardiac inflammation and injury in viral myocarditis. Electronic supplementary material The online version of this article (doi:10.1007/s00018-016-2423-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marieke Rienks
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
| | - Anna Papageorgiou
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.,Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany
| | - Kristiaan Wouters
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
| | - Wouter Verhesen
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
| | - Rick van Leeuwen
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
| | - Paolo Carai
- Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany
| | - Georg Summer
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
| | - Dirk Westermann
- Centre for Cardiology Research, Hamburg University, Leuven, Belgium
| | - Stephane Heymans
- Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.,Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany
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Hamann L, Glaeser C, Schulz S, Gross M, Franke A, Nöthlings U, Schumann RR. A micro RNA-146a polymorphism is associated with coronary restenosis. Int J Immunogenet 2014; 41:393-6. [PMID: 25053223 DOI: 10.1111/iji.12136] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/09/2014] [Accepted: 06/12/2014] [Indexed: 02/06/2023]
Abstract
The association of the miRNA-146a polymorphism rs2910164 with atherosclerosis and restenosis was investigated. We found no association with atherosclerosis; however, we found a negative association for the G/C (P = 0.007) and a positive association for the C/C genotype with the risk of restenosis, which is the main drawback for cardiac surgery.
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Affiliation(s)
- L Hamann
- Institute of Microbiology and Hygiene, Charité University Medical Center, Berlin, Germany
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6
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Sun Q, Li J, Gao F. New insights into insulin: The anti-inflammatory effect and its clinical relevance. World J Diabetes 2014; 5:89-96. [PMID: 24765237 PMCID: PMC3992527 DOI: 10.4239/wjd.v5.i2.89] [Citation(s) in RCA: 167] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 03/04/2014] [Indexed: 02/05/2023] Open
Abstract
Hyperglycemia, a commonly exhibited metabolic disorder in critically ill patients, activates the body’s inflammatory defense mechanism, causing the waterfall release of numerous inflammatory mediators and cytokines, and eventually leads to organ damage. As the only glucose-lowering hormone in the body, insulin not only alleviates the detrimental effects of hyperglycemia through its metabolic regulation, but also directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence. In this sense, hyperglycemia is pro-inflammatory whereas insulin is anti-inflammatory. Therefore, during the past 50 years, insulin has not only been used in the treatment of diabetes, but has also been put into practical use in dealing with cardiovascular diseases and critical illnesses. This review summarizes the recent advances regarding the anti-inflammatory effects of insulin in both basic research and clinical trials, with the hope of aiding in the design of further experimental research and promoting effective insulin administration in clinical practice.
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Lee HR, Jun HK, Choi BK. Tannerella forsythia BspA increases the risk factors for atherosclerosis in ApoE(-/-) mice. Oral Dis 2013; 20:803-8. [PMID: 24372897 DOI: 10.1111/odi.12214] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 11/04/2013] [Accepted: 11/18/2013] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the effects of Tannerella forsythia and its major surface virulence factor, BspA, on the progression of atherosclerosis in ApoE(-/-) mice and the expression of lipid metabolism-related genes. METHODS PMA-differentiated THP-1 cells were treated with BspA to detect foam cell formation. The proximal aortas of ApoE(-/-) mice injected with T. forsythia or BspA were stained with oil red O to examine lipid deposition. The serum levels of CRP, HDL, and LDL were detected by ELISA. The liver tissue of T. forsythia- or BspA-injected ApoE(-/-) mice was examined for mRNA expression of lipid metabolism-related genes, such as liver X receptors (LXRα and LXRβ) and ATP-binding cassette transporter A1 (ABCA1). RESULTS Tannerella forsythia and BspA induced foam cell formation in THP-1 cells and accelerated the progression of atherosclerotic lesions in ApoE(-/-) mice. Mouse serum levels of CRP and LDL were increased, and HDL was decreased by T. forsythia and BspA. The expression levels of LXRα and LXRβ, and ABCA1 in liver tissue were decreased by T. forsythia and BspA. CONCLUSIONS Tannerella forsythia and BspA augmented atherosclerotic lesion progression in ApoE(-/-) mice. This process may be associated with downregulation of lipid metabolism-related gene expression.
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Affiliation(s)
- H R Lee
- Division of High-Risk Pathogen Research, Center for Infectious Diseases, National Institute of Health, Cheongwon-gun, Chungbuk, Korea
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8
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Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2013; 305:L934-42. [DOI: 10.1152/ajplung.00034.2013] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-κB-mediated signal transduction. CRP-induced NF-κB activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-κB pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-κB kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-κBp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-κB pathway in mediating different effects of CRP on proximal CTEPH-PAEC.
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Affiliation(s)
- Marijke Wynants
- Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Leanda Vengethasamy
- Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Alicja Ronisz
- Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
| | - Bart Meyns
- Cardiac Surgery Department, University Hospitals of Leuven, Leuven, Belgium; and
| | - Marion Delcroix
- Respiratory Division, University Hospitals and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - Rozenn Quarck
- Respiratory Division, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
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Wang XX, Lv XX, Wang JP, Yan HM, Wang ZY, Liu HZ, Fu XM, Hu ZW. Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice. Acta Pharmacol Sin 2013; 34:1025-35. [PMID: 23852085 DOI: 10.1038/aps.2013.75] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Accepted: 05/09/2013] [Indexed: 01/04/2023]
Abstract
AIM Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis. METHODS Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined. RESULTS Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice. CONCLUSION The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.
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Zhang H, Taylor WR, Joseph G, Caracciolo V, Gonzales DM, Sidell N, Seli E, Blackshear PJ, Kallen CB. mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells. Arterioscler Thromb Vasc Biol 2013; 33:1212-20. [PMID: 23559629 DOI: 10.1161/atvbaha.113.301496] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE We studied the expression and function of an mRNA-binding protein, zinc finger protein-36 (ZFP36), in vascular endothelial cells in vivo and in vitro. We tested the hypotheses that ZFP36 regulates inflammation in vascular endothelial cells and that it functions through direct binding to target cytokine mRNAs. We also tested whether ZFP36 inhibits nuclear factor-κB-mediated transcriptional responses in vascular endothelial cells. APPROACH AND RESULTS ZFP36 was minimally expressed in healthy aorta but was expressed in endothelial cells overlying atherosclerotic lesions in mice and humans. The protein was also expressed in macrophage foam cells of atherosclerosis. ZFP36 was expressed in human aortic endothelial cells in response to bacterial lipopolysaccharide, glucocorticoid, and forskolin, but not oxidized low-density lipoproteins or angiotensin II. Functional studies demonstrated that ZFP36 reduces the expression of inflammatory cytokines in target cells by 2 distinct mechanisms: ZFP36 inhibits nuclear factor-κB transcriptional activation and also binds to cytokine mRNAs, leading to reduced transcript stability. CONCLUSIONS ZFP36 is expressed in vascular endothelial cells and macrophage foam cells where it inhibits the expression of proinflammatory mRNA transcripts. The anti-inflammatory effects of ZFP36 in endothelial cells occur via both transcriptional and posttranscriptional mechanisms. Our data suggest that enhancing vascular ZFP36 expression might reduce vascular inflammation.
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Affiliation(s)
- Huanchun Zhang
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA, USA
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11
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The crucial role of the MyD88 adaptor protein in the inflammatory response induced by Bothrops atrox venom. Toxicon 2013; 67:37-46. [PMID: 23474268 DOI: 10.1016/j.toxicon.2013.02.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 02/12/2013] [Indexed: 12/12/2022]
Abstract
Most snake accidents in North Brazil are attributed to Bothrops atrox, a snake species of the Viperidae family whose venom simultaneously induces local and systemic effects in the victims. The former are clinically more important than the latter, as they cause severe tissue lesions associated with strong inflammatory responses. Although several studies have shown that inflammatory mediators are produced in response to B. atrox venom (BaV), there is little information concerning the molecular pathways involved in innate immune system signaling. Myeloid differentiation factor 88 (MyD88) is an adaptor molecule responsible for transmitting intracellular signals from most toll-like receptors (TLRs) after they interact with pathogen-associated molecular patterns (PAMPs) or other stimuli such as endogenous damage-associated molecular patterns (DAMPs). The MyD88-dependent pathway leads to activation of transcription factors, which in turn induce synthesis of inflammatory mediators such as eicosanoids, cytokines and chemokines. The aim of this study was to investigate the involvement of MyD88 on the acute inflammatory response induced by BaV. Wild-type (WT) C57BL/6 mice and MyD88 knockout (MyD88(-/-)) mice were intraperitoneally injected with BaV. Compared to WT mice, MyD88(-/-) animals showed an impaired inflammatory response to BaV, with lower influx of polymorphonuclear and mononuclear cells to the peritoneal cavity. Furthermore, peritoneal leukocytes from BaV-injected MyD88(-/-) mice did not induce COX-2 or LTB4 protein expression and released low concentrations of PGE2. These mice also failed to produce Th1 and Th17 cytokines and CCL-2, but IL-10 levels were similar to those of BaV-injected WT mice. Our results indicate that MyD88 signaling is required for activation of the inflammatory response elicited by BaV, raising the possibility of developing new therapeutic targets to treat Bothrops sp. poisoning.
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12
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Lu Z, Li Y, Jin J, Zhang X, Lopes-Virella MF, Huang Y. Toll-like receptor 4 activation in microvascular endothelial cells triggers a robust inflammatory response and cross talk with mononuclear cells via interleukin-6. Arterioscler Thromb Vasc Biol 2012; 32:1696-706. [PMID: 22596222 DOI: 10.1161/atvbaha.112.251181] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE It is known that toll-like receptor 4 (TLR4) plays an important role in atherosclerosis. Because both microvascular (MIC) and macrovascular (MAC) endothelial cells (ECs) are present in atherosclerotic lesions, the present study compared TLR4-triggered inflammatory response and cross talk with mononuclear cells between MIC and MAC ECs. METHODS AND RESULTS ELISA, real-time polymerase chain reaction, and gene expression profiling showed that TLR4 activation by lipopolysaccharide stimulated a much higher expression of inflammatory genes including cytokines, chemokines, growth factors, and adhesion molecules in MIC ECs than MAC ECs. Furthermore, coculture studies showed that TLR4 activation in MIC ECs, but not MAC ECs, induced a cross talk with U937 mononuclear cells through MIC EC-released interleukin-6 to upregulate matrix metalloproteinase-1 expression in U937 cells. To explore molecular mechanisms underlying the different responses to TLR4 activation between MIC and MAC ECs, we showed that MIC ECs had a higher expression of TLR4 and CD14 and a higher TLR4-mediated nuclear factor-kappaB activity than MAC ECs. CONCLUSIONS The present study showed that TLR4 activation triggers a more robust inflammatory response in MIC ECs than MAC ECs. Given the importance of inflammatory cytokines and matrix metalloproteinases in plaque rupture, MIC ECs may play a key role in plaque destabilization through a TLR4-dependent mechanism.
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Affiliation(s)
- Zhongyang Lu
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA
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13
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Feng Y, Chao W. Toll-like receptors and myocardial inflammation. Int J Inflam 2011; 2011:170352. [PMID: 21977329 PMCID: PMC3182762 DOI: 10.4061/2011/170352] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2011] [Revised: 05/24/2011] [Accepted: 06/12/2011] [Indexed: 12/22/2022] Open
Abstract
Toll-like receptors (TLRs) are a member of the innate immune system. TLRs detect invading pathogens through the pathogen-associated molecular patterns (PAMPs) recognition and play an essential role in the host defense. TLRs can also sense a large number of endogenous molecules with the damage-associated molecular patterns (DAMPs) that are produced under various injurious conditions. Animal studies of the last decade have demonstrated that TLR signaling contributes to the pathogenesis of the critical cardiac conditions, where myocardial inflammation plays a prominent role, such as ischemic myocardial injury, myocarditis, and septic cardiomyopathy. This paper reviews the animal data on (1) TLRs, TLR ligands, and the signal transduction system and (2) the important role of TLR signaling in these critical cardiac conditions.
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Affiliation(s)
- Yan Feng
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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14
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Hofmann U, Ertl G, Frantz S. Toll-like receptors as potential therapeutic targets in cardiac dysfunction. Expert Opin Ther Targets 2011; 15:753-65. [PMID: 21385118 DOI: 10.1517/14728222.2011.566560] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The innate immune system can detect the highly conserved, relatively invariant structural motifs of pathogens. The most important innate immune receptors, Toll-like receptors (TLRs), represent a first line of defense against infectious pathogens, and play a pivotal role in initiating and shaping innate and adaptive immune responses. TLRs are not only expressed in immune cells, but also in cardiovascular cells. In addition to their role in response to microbial infections, evidence suggests that TLRs can also recognize endogenous ligands and may play a role in mediating cardiomyocyte cell death and survival after non-infectious injury. AREAS COVERED TLRs could be a link between cardiovascular diseases and the immune system. Experimentally, there is good evidence that TLR activation contributes to development and progression of both acute cardiac injury and chronic heart failure. The role of TLRs in myocardial ischemia-reperfusion, remodeling, septic cardiomyoparthy, autoimmune- and viral myocarditis, anthracycline-induced cardiomyopathy and cardiac hypertrophy, in basic as well as clinical science are discussed. EXPERT OPINION Evidence, mainly from animal experiments, indicates that TLRs contribute to all of the myocardial disease states reviewed in this paper. However, the relevance of TLRs as therapeutic targets remains to be defined as clinical data is sparse.
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Affiliation(s)
- Ulrich Hofmann
- University Hospital Würzburg, Department of Internal Medicine I, Oberdürrbacherstraße 6, 97080 Würzburg, Germany
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15
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López J, Fernández-Pisonero I, Dueñas AI, Maeso P, San Román JA, Crespo MS, García-Rodríguez C. Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells. Int J Cardiol 2011; 158:18-25. [PMID: 21247641 DOI: 10.1016/j.ijcard.2010.12.089] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2010] [Revised: 11/23/2010] [Accepted: 12/23/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND Aortic stenosis shares some ethiopathological features with atherosclerosis and increasing evidence links Toll-like receptors (TLRs) to atherogenesis. METHODS TLR-mediated inflammation and osteogenesis were investigated in human interstitial cells isolated from stenotic and non-stenotic aortic valves. TLR expression and signalling were evaluated by quantitative RT-PCR, flow cytometry, Western blot analysis, ELISA, and cytokine arrays. Osteogenesis was evaluated by measuring alkaline phosphatase activity. RESULTS Interstitial cells from control valves express most TLRs, being TLR4 the most abundant, whereas cells from stenotic valves express higher TLR4 and TLR2 and lower TLR5 and TLR9 transcript levels. When pro-inflammatory pathways were analyzed, we observed that TLR4, TLR2 and TLR3 ligands induced an early activation of NF-κB and p38 MAPK activation in cells from control and stenotic valves. Strikingly, when TLRs sensing viral patterns were studied, a sustained TLR3-mediated activation of NF-κB, a κB-independent induction of catalytically active cyclooxigenase (COX)-2 and ICAM-1 expression, and induction of expression of several chemokines were observed. TLR4, but not TLR2, engagement produced a similar but NF-κB-dependent effect. Moreover, TLR3 and TLR4 agonists induced alkaline phosphatase expression and activity. CONCLUSIONS Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis.
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Affiliation(s)
- Javier López
- Instituto Ciencias del Corazón (ICICOR), Valladolid, Spain
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16
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Serezani CH, Lewis C, Jancar S, Peters-Golden M. Leukotriene B4 amplifies NF-κB activation in mouse macrophages by reducing SOCS1 inhibition of MyD88 expression. J Clin Invest 2011; 121:671-82. [PMID: 21206089 DOI: 10.1172/jci43302] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Accepted: 11/03/2010] [Indexed: 12/28/2022] Open
Abstract
Activation of NF-κB and 5-lipoxygenase-mediated (5-LO-mediated) biosynthesis of the lipid mediator leukotriene B4 (LTB4) are pivotal components of host defense and inflammatory responses. However, the role of LTB4 in mediating innate immune responses elicited by specific TLR ligands and cytokines is unknown. Here we have shown that responses dependent on MyD88 (an adaptor protein that mediates signaling through all of the known TLRs, except TLR3, as well as IL-1β and IL-18) are reduced in mice lacking either 5-LO or the LTB4 receptor BTL1, and that macrophages from these mice are impaired in MyD88-dependent activation of NF-κB. This macrophage defect was associated with lower basal and inducible expression of MyD88 and reflected impaired activation of STAT1 and overexpression of the STAT1 inhibitor SOCS1. Expression of MyD88 and responsiveness to the TLR4 ligand LPS were decreased by Stat1 siRNA silencing in WT macrophages and restored by Socs1 siRNA in 5-LO-deficient macrophages. These results uncover a pivotal role in macrophages for the GPCR BLT1 in regulating activation of NF-κB through Stat1-dependent expression of MyD88.
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Affiliation(s)
- Carlos H Serezani
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-5642, USA.
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17
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Aoki T, Nishimura M, Ishibashi R, Kataoka H, Takagi Y, Hashimoto N. Toll-like receptor 4 expression during cerebral aneurysm formation. Laboratory investigation. J Neurosurg 2010; 113:851-8. [PMID: 19852543 DOI: 10.3171/2009.9.jns09329] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECT The pathophysiological origin of cerebral aneurysms is closely associated with chronic inflammation in arterial walls. Recently, the authors identified nuclear factor-kappa B (NF-κB) as a key mediator of cerebral aneurysm formation and progression. Because Toll-like receptor 4 (TLR4) stimulates NF-κB activation in arterial walls in atherosclerosis, the authors hypothesize that TLR4 expresses in cerebral aneurysms and contributes to the activation of NF-κB in cerebral aneurysm walls. METHODS Cerebral aneurysms were induced in male Sprague-Dawley rats. Expression of TLRs in cerebral aneurysm walls was assessed using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of TLR4 was examined using RT-PCR, immunohistochemical studies, and Western blotting. To assess TLR4 dependency on NF-κB activation, double immunostaining and a study using NF-κB-deficient mice were done. Finally, TLR4 expression in human cerebral aneurysm walls was assessed using immunohistochemical studies. RESULTS In cerebral aneurysm walls, TLR1, -4, -5, -6, -10, and -11 were expressed. Among them, TLR4 and TLR10 expression changed during cerebral aneurysm formation. Expression of TLR4 was predominantly in the endothelial cell layer of cerebral aneurysm walls, and was transitionally upregulated at the early stage of cerebral aneurysm formation. The TLR4 expression coincided well with NF-κB activation. In human cerebral aneurysms, TLR4 was also expressed in the endothelial cell layer, as it was in rats. CONCLUSIONS Toll-like receptor 4 was expressed in cerebral aneurysm walls both in rats and humans. This receptor may play a crucial role in cerebral aneurysm formation through NF-κB activation in endothelial cells. The results of the present study will shed new light on the pathogenesis of cerebral aneurysm formation.
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Affiliation(s)
- Tomohiro Aoki
- Department of Neurosurgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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18
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Heo SK, Yi HS, Yun HJ, Ko CH, Choi JW, Park SD. Ethylacetate extract from Draconis Resina inhibits LPS-induced inflammatory responses in vascular smooth muscle cells and macrophages via suppression of ROS production. Food Chem Toxicol 2010; 48:1129-36. [DOI: 10.1016/j.fct.2009.06.043] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2009] [Revised: 06/24/2009] [Accepted: 06/26/2009] [Indexed: 01/04/2023]
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Sorrentino R, Morello S, Chen S, Bonavita E, Pinto A. The activation of liver X receptors inhibits toll-like receptor-9-induced foam cell formation. J Cell Physiol 2010; 223:158-67. [PMID: 20049870 DOI: 10.1002/jcp.22022] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Toll-like receptors (TLRs) are related to foam cell formation (FCF), key event in the establishment/progression of atherosclerosis. The activation of TLR2 and TLR4 can increase FCF. The aim of this study was to evaluate the role of TLR9 in FCF. Murine macrophages were treated with CpG-ODN, TLR9 agonist, and oxidized particles of LDL (Paz-PC) and FCF was analyzed by means of Oil Red O staining. The administration of CpG-ODN plus Paz-PC onto macrophages increased the amount of lipid droplets, correlated to increased levels of tumor necrosis factor (TNF)-alpha, IFNbeta, and IP-10. The underlying mechanism by which TLR9 ligation influenced Paz-PC in the FCF was NF-kappaB- and IRF7-dependent, as observed by higher levels of phosphorylated IkappaBalpha, increased nuclear translocation of the p65 subunit, lower levels of the total IKKalpha protein and higher release of interferon-dependent cytokines, such as IP-10. Liver X receptors (LXRs) regulate lipid cellular transport and negatively modulate TLR-dependent signaling pathways. Indeed, the addition of GW3965, synthetic LXRs agonist, significantly reduced FCF after CpG-ODN plus Paz-PC stimulation. In this condition, we observed decreased levels of the nuclear translocation of the p65 subunit, related to the higher presence of LXRalpha into the nucleus. TNF-alpha, IP-10, and IFNbeta levels were reduced by the administration of GW3965 following CpG-ODN and Paz-PC treatment. In conclusion, the activation of TLR9 facilitates the formation of foam cells in an NF-kappaB- and IRF7-dependent manner, countered by the activation of LXRs. This study further support LXRs as potential anti-atherosclerotic target.
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Affiliation(s)
- Rosalinda Sorrentino
- Pharmaceutical Science Department, University of Salerno, 84084 Fisciano, Salerno, Italy.
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Lee SH, Park DW, Park SC, Park YK, Hong SY, Kim JR, Lee CH, Baek SH. Calcium-independent phospholipase A2beta-Akt signaling is involved in lipopolysaccharide-induced NADPH oxidase 1 expression and foam cell formation. THE JOURNAL OF IMMUNOLOGY 2009; 183:7497-504. [PMID: 19917703 DOI: 10.4049/jimmunol.0900503] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Foam cell formation is the most important process in atherosclerosis, and low density lipoprotein oxidation by reactive oxygen species (ROS) is the key step in the conversion of macrophages to foam cells. This study reveals the control mechanism of the gene for NADPH oxidase 1 (Nox1), which produces ROS in the formation of foam cells by stimulating TLR4. Treatment of macrophages by the TLR4 agonist LPS stimulated ROS production and ROS-mediated macrophage to foam cell conversion. This LPS-induced ROS production and foam cell formation could be abrogated by pretreatment of macrophages with N-acetyl cysteine or apocynin. LPS increased Nox1 promoter activity, and resultant expression of mRNA and protein. Small interfering RNA mediated inhibition of Nox1 expression decreased LPS-induced ROS production and foam cell formation. LPS-mediated Nox1 expression and the responses occurred in a calcium-independent phospholipase A(2) (iPLA(2))-dependent manner. The iPLA(2)beta-specific inhibitor S-BEL or iPLA(2)beta small interfering RNA attenuated LPS-induced Nox1 expression, ROS production, and foam cell formation. In addition, activation of iPLA(2)beta by LPS caused Akt phosphorylation and was followed by increased Nox1 expression. These results suggest that the binding of LPS and TLR4 increases Nox1 expression through the iPLA(2)beta-Akt signaling pathway, and control ROS production and foam cell formation.
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Affiliation(s)
- Sun-Hye Lee
- Aging-associated Vascular Disease Research Center, Department of Biochemistry and Molecular Biology, College of Medicine, Yeungnam University, Daegu, South Korea
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21
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Anti-inflammatory action of apoptotic cells in patients with acute coronary syndromes. Atherosclerosis 2009; 205:391-5. [DOI: 10.1016/j.atherosclerosis.2008.12.042] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2008] [Revised: 12/27/2008] [Accepted: 12/28/2008] [Indexed: 01/04/2023]
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Coenen KR, Gruen ML, Lee-Young RS, Puglisi MJ, Wasserman DH, Hasty AH. Impact of macrophage toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice. Diabetologia 2009; 52:318-28. [PMID: 19052722 PMCID: PMC2615827 DOI: 10.1007/s00125-008-1221-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2008] [Accepted: 10/21/2008] [Indexed: 12/23/2022]
Abstract
AIMS/HYPOTHESIS Toll-like receptor 4 (TLR4) is a receptor for saturated fatty acids (SFAs), global deficiency of which has been shown to protect against inflammation, insulin resistance and atherosclerotic lesion formation. Because macrophages express Tlr4 and are important in insulin resistance and atherosclerotic lesion formation due to their infiltration of white adipose tissue (WAT) and the artery wall, respectively, we hypothesised that deficiency of macrophage TLR4 could protect against these disorders. METHODS Bone marrow transplantation of agouti, LDL-receptor deficient (A(y)/a; Ldlr (-/-)) mice with marrow from either C57BL/6 or Tlr4 (-/-) mice was performed. Recipient mice with Tlr4 (+/+) marrow (MthetaTLR4(+/+)) or with Tlr4 (-/-) marrow (MthetaTLR4(-/-)) were then placed on one of four diets: (1) low fat; (2) high fat; (3) high fat rich in SFAs (HF(SFA)); and (4) HF(SFA) supplemented with fish oil. RESULTS There were no differences in body composition or plasma lipids between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice on any of the diets. However, we observed a decrease in some macrophage and inflammatory markers in WAT of female low fat-fed MthetaTLR4(-/-) mice compared with MthetaTLR4(+/+) mice. MthetaTLR4(-/-) mice fed low-fat diet also displayed decreased atherosclerotic lesion area. There were no differences in macrophage accrual in WAT or atherosclerosis between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice fed any of the high-fat diets. Finally, no difference was seen in insulin sensitivity between MthetaTLR4(+/+) and MthetaTLR4(-/-) mice fed the HF(SFA) diet. CONCLUSIONS/INTERPRETATION These data suggest that under certain dietary conditions, macrophage expression of Tlr4 can be an important mediator of macrophage accumulation in WAT and the artery wall.
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Affiliation(s)
- Kimberly R. Coenen
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
| | - Marnie L. Gruen
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
| | - Robert S. Lee-Young
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
| | - Michael J. Puglisi
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
| | - David H. Wasserman
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
| | - Alyssa H. Hasty
- Vanderbilt University Medical Centre, Department of Molecular Physiology & Biophysics, Nashville, TN 37232
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Antigen-induced immunomodulation in the pathogenesis of atherosclerosis. Clin Dev Immunol 2008; 2008:723539. [PMID: 18551190 PMCID: PMC2423423 DOI: 10.1155/2008/723539] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2007] [Revised: 04/02/2008] [Accepted: 04/30/2008] [Indexed: 12/16/2022]
Abstract
Atherosclerosis is a chronic inflammatory disorder characterised by the accumulation of monocytes/macrophages, smooth muscle cells, and lymphocytes within the arterial wall in response to the release of proinflammatory molecules. Such accumulation results in the formation of the atherosclerotic plaque, which would eventually evolve to complications such as total artery occlusion, rupture, calcification, or aneurysm. Although the molecular mechanism responsible for the development of atherosclerosis is not completely understood, it is clear that the immune system plays a key role in the development of the atherosclerotic plaque and in its complications. There are multiple antigenic stimuli that have been associated with the pathogenesis of atherosclerosis. Most of these stimuli come from modified self-molecules such as oxidised low-density lipoproteins (oxLDLs), beta2glycoprotein1 (β2GP1), lipoprotein a (LP(a)), heat shock proteins (HSPs), and protein components of the extracellular matrix such as collagen and fibrinogen in the form of advanced glycation-end (AGE) products. In addition, several foreign antigens including bacteria such as Porphyromonas gingivalis and Chlamydia pneumoniae and viruses such as enterovirus and cytomegalovirus have been associated with atherosclerosis as potentially causative or bystander participants, adding another level of complexity to the analysis of the pathophysiology of atherosclerosis. The present review summarises the most important scientific findings published within the last two decades on the importance of antigens, antigen stimulation, and adaptive immune responses in the development of atherosclerotic plaques.
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24
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Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451:904-13. [PMID: 18288179 DOI: 10.1038/nature06796] [Citation(s) in RCA: 374] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Atherosclerosis is characterized by the thickening of the arterial wall and is the primary cause of coronary artery disease and cerebrovascular disease, two of the most common causes of illness and death worldwide. Clinical trials have confirmed that certain lipoproteins and the renin-angiotensin-aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease, and that interventions targeted towards these are beneficial. Furthermore, efforts to understand how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as to understand the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy.
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Affiliation(s)
- Daniel J Rader
- Cardiovascular Institute and Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 654 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA.
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Han JW, Shimada K, Ma-Krupa W, Johnson TL, Nerem RM, Goronzy JJ, Weyand CM. Vessel Wall–Embedded Dendritic Cells Induce T-Cell Autoreactivity and Initiate Vascular Inflammation. Circ Res 2008; 102:546-53. [DOI: 10.1161/circresaha.107.161653] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Human medium-sized and large arteries are targeted by inflammation with innate and adaptive immune responses occurring within the unique microspace of the vessel wall. How 3D spatial arrangements influence immune recognition and cellular response thresholds and which cell populations sense immunoactivating ligands and function as antigen-presenting cells are incompletely understood. To mimic the 3D context of human arteries, bioartificial arteries were engineered from collagen type I matrix, human vascular smooth muscle cells (VSMCs), and human endothelial cells and populated with cells implicated in antigen presentation and T-cell stimulation, including monocytes, macrophages, and myeloid dendritic cells (DCs). Responsiveness of wall-embedded antigen-presenting cells was probed with the Toll-like receptor ligand lipopolysaccharide, and inflammation was initiated by adding autologous CD4
+
T cells. DCs colonized the outermost VSMC layer, recapitulating their positioning at the media–adventitia border of normal arteries. Wall-embedded DCs responded to the microbial product lipopolysaccharide by entering the maturation program and upregulating the costimulatory ligand CD86. Activated DCs effectively stimulated autologous CD4 T cells, which produced the proinflammatory cytokine interferon-γ and infiltrated deeply into the VSMC layer, causing matrix damage. Lipopolysaccharide-triggered macrophages were significantly less efficacious in recruiting T cells and promoting T-cell stimulation. CD14
+
monocytes, even when preactivated, failed to support initial steps of vascular wall inflammation. Innate immune cells, including monocytes, macrophages, and DCs, display differential functions in the vessel wall. DCs are superior in sensing pathogen-derived motifs and are highly efficient in breaking T-cell tolerance, guiding T cells toward proinflammatory and tissue-invasive behavior.
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Affiliation(s)
- Ji W. Han
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Kazunori Shimada
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Wei Ma-Krupa
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Tiffany L. Johnson
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Robert M. Nerem
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Jörg J. Goronzy
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
| | - Cornelia M. Weyand
- From the Kathleen B. and Mason I. Lowance Center for Human Immunology (J.W.H., K.S., W.M.-K., J.J.G., C.M.W.), Department of Medicine, Emory University School of Medicine, Atlanta, Ga; and Parker H. Petit Institute for Bioengineering and Bioscience (T.L.J., R.M.N.), Georgia Institute of Technology, Atlanta
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Zhong J, Kyriakis JM. Dissection of a signaling pathway by which pathogen-associated molecular patterns recruit the JNK and p38 MAPKs and trigger cytokine release. J Biol Chem 2007; 282:24246-54. [PMID: 17584736 DOI: 10.1074/jbc.m703422200] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Pathogen-associated molecular patterns (PAMPs), molecular moieties produced by invading microbial pathogens, initiate innate immune responses by binding to pattern recognition receptors (PRRs). Engagement of PRRs elicits a wide variety of responses, including the production and release of cytokines and chemokines. These responses require the activation of several parallel signaling pathways, including NF-kappaB, the interferon regulatory factors, and the MAPKs. The JNK and p38 MAPK groups are major PRR effectors and are key to the PRR-dependent induction and release of proinflammatory cytokines such as tumor necrosis factor and interleukin-8. The mammalian Ste20 orthologue germinal center kinase (GCK) is required for the activation of JNK by a subset of PAMPs; however, the mechanisms by which GCK couples to downstream events remain unclear. Here we show that GCK is required for JNK and, unexpectedly, p38 activation by three bacterial PAMPs, lipopolysaccharide, peptidoglycan, and flagellin (FliC). We show that these same PAMPs, in a GCK-dependent manner, activate mixed lineage kinases-2 and -3, MAPK kinase kinases upstream of JNK, and p38. We also show that MLK2 and -3 are required for activation of JNK and p38 by ectopically expressed GCK. Finally, we show that MLK2 and -3 are required for lipopolysaccharide, peptidoglycan, and FliC recruitment of JNK and p38 as well as for PAMP recruitment of the transcription factor c-Jun, and for the induction of interleukin-8. Our results define a signaling pathway whereby PAMPs can trigger MAPK activation and gene expression.
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Affiliation(s)
- Jian Zhong
- Molecular Cardiology Research Institute, Department of Medicine, Tufts-New England Medical Center and the Boston, Massachusetts 02111, USA
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Zhou ML, Wu W, Ding YS, Zhang FF, Hang CH, Wang HD, Cheng HL, Yin HX, Shi JX. Expression of Toll-like receptor 4 in the basilar artery after experimental subarachnoid hemorrhage in rabbits: a preliminary study. Brain Res 2007; 1173:110-6. [PMID: 17826750 DOI: 10.1016/j.brainres.2007.07.059] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2007] [Revised: 07/23/2007] [Accepted: 07/26/2007] [Indexed: 12/20/2022]
Abstract
Inflammation and immunity play a crucial role in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). Recently, a growing body of evidence indicates that Toll-like receptor (TLR) 4 is vital for inflammation and immunity. Therefore, this study aimed to detect the expression of TLR4 in the basilar artery in a rabbit SAH model and to clarify the potential role of TLR4 in cerebral vasospasm. A total of 48 rabbits were randomly divided into four groups: control group; day 3, day 5, and day 7 groups. Day 3, day 5, and day 7 groups were all SAH groups. The animals in day 3, day 5 and day 7 groups were subjected to injection of autologous blood into cisterna magna twice on day 0 and day 2 and were killed on days 3, 5, and 7, respectively. Cross-sectional area of basilar artery was measured and the TLR4 expression was assessed by immunohistochemistry and Western blot analysis. The basilar arteries exhibited vasospasm after SAH and became more severe on day 3 and 5. The elevated expression of TLR4 was detected after SAH and peaked on day 3 and 5. TLR4 is increasingly expressed in a parallel time course to the development of cerebral vasospasm in a rabbit experimental model of SAH.
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Affiliation(s)
- Meng-liang Zhou
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province, China
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Kawamura A, Baitsch D, Telgmann R, Feuerborn R, Weissen-Plenz G, Hagedorn C, Saku K, Brand-Herrmann SM, von Eckardstein A, Assmann G, Nofer JR. Apolipoprotein E interrupts interleukin-1beta signaling in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2007; 27:1610-7. [PMID: 17510469 DOI: 10.1161/atvbaha.106.129957] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVES Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1beta (IL-1beta), a proinflammatory cytokine present in atherosclerotic lesions. METHODS AND RESULTS IL-1beta-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-kappaB and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1beta signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1beta signaling intermediates revealed that NF-kappaB transactivation was inhibited by apoE in MyD88- and IRAK1- but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1beta signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1beta signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-alpha or polyinosinic:polycytidylic acid. CONCLUSION ApoE targets IRAK-1 activation and thereby interrupts IL-1beta and IL-18 signaling in VSMCs. This antiinflammatory effect represents a novel antiatherogenic activity of apoE.
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Affiliation(s)
- Akira Kawamura
- Department of Lipid Metabolism, Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Germany
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