Myeloid-Related Protein-8/14 Is Critical for the Biological Response to Vascular Injury

Croce, Kevin; Gao, Hanyu; Wang, Yunmei; Mooroka, Toshifumi; Sakuma, Masashi; Shi, Chun; Sukhova, Galina K.; Packard, René R. Sevag; Hogg, Nancy; Libby, Peter; Simon, Daniel I.

doi:10.1161/circulationaha.108.814582

Cited by 226 publications

(198 citation statements)

References 42 publications

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“…Targeted deletion of these genes in mice results in a significant phenotype under inflammatory conditions such as autoimmune diseases, arthritis, infections, LPSinduced shock, and allergies (12,43). Expression of these proteins in humans correlates very well with disease activity, especially in predicting the response to therapy for arthritis and inflammatory bowel disease, as well as the risk of flares in remitting-relapsing disease courses (7, 8, 11).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

Fassl¹,

Austermann²,

Papantonopoulou

et al. 2015

The Journal of Immunology

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The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products–dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

Fassl¹,

Austermann²,

Papantonopoulou

et al. 2015

The Journal of Immunology

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“…S100A8 forms a heterodimer with S100A9, and the complex is one of the most powerful endogenous ligands for TLR4, which is essential for full activation of macrophages endotoxin-induced shock and vascular and autoimmune disorders [24,31,32]. TLR4 signalling also plays an important role in the development of various kidney diseases, yet the role of TLR4 in diabetic glomerulopathy or hyperlipidaemiainduced kidney damage remains to be elucidated [8][9][10][11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

et al. 2012

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Aims/hypothesis Hyperlipidaemia is an independent risk factor for the progression of diabetic nephropathy, but its molecular mechanism remains elusive. We investigated in mice how diabetes and hyperlipidaemia cause renal lesions separately and in combination, and the involvement of Toll-like receptor 4 (TLR4) in the process. Methods Diabetes was induced in wild-type (WT) and Tlr4 knockout (KO) mice by intraperitoneal injection of streptozotocin (STZ). At 2 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Functional and histological analyses were carried out 6 weeks later. Results Compared with treatment with STZ or HFD alone, treatment of WT mice with both STZ and HFD markedly aggravated nephropathy, as indicated by an increase in albuminuria, mesangial expansion, infiltration of macrophages and upregulation of pro-inflammatory and extracellularmatrix-associated gene expression in glomeruli. In Tlr4 KO mice, the addition of an HFD to STZ had almost no effects on the variables measured. Production of protein S100 calcium binding protein A8 (calgranulin A; S100A8), a potent ligand for TLR4, was observed in abundance in macrophages infiltrating STZ-HFD WT glomeruli and in glomeruli of diabetic nephropathy patients. High-glucose and fatty acid treatment synergistically upregulated S100a8 gene expression in macrophages from WT mice, but not from KO mice. As putative downstream targets of TLR4, phosphorylation of interferon regulatory factor 3 (IRF3) was enhanced in kidneys of WT mice co-treated with STZ and HFD. Conclusions/interpretation Activation of S100A8/TLR4 signalling was elucidated in an animal model of diabetic glomerular injury accompanied with hyperlipidaemia, which may provide novel therapeutic targets in progressive diabetic nephropathy.

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“…8), although the molecular pathways that lead from uPA expression to S100A8/A9 up-regulation remain to be defined. S100A8/A9 are excellent candidate mediators of accelerated atherosclerosis in SR-uPA mice and of uPA/Plg-mediated atherogenesis in humans because they are present in human and mouse lesions and are atherogenic in mice (53)(54)(55). S100A8/A9 potentially accelerate atherosclerosis via chemoattractant and proinflammatory activities that include binding to the RAGE and TLR4, activation of NF-B, and up-regulation of the adhesion molecule CD11b in circulating monocytes (56 -58).…”

Section: Upa-induced Atherosclerosis and Aortic Dilationmentioning

confidence: 99%

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

Farris

Krishnan

et al. 2011

Journal of Biological Chemistry

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Data from clinical studies, cell culture, and animal models implicate the urokinase plasminogen activator (uPA)/uPA receptor (uPAR)/plasminogen system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/uPAR/plasminogen stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression and mice genetically deficient in uPAR to elucidate mechanisms of uPA/uPAR/plasminogen-accelerated atherosclerosis and aneurysm formation. We found that macrophage-specific uPA overexpression accelerates atherosclerosis and causes aortic root dilation in fat-fed Ldlr ؊/؊ mice (as we previously reported in Apoe ؊/؊ mice). Macrophage-expressed uPA accelerates atherosclerosis by stimulation of lesion progression rather than initiation and causes disproportionate lipid accumulation in early lesions. uPA-accelerated atherosclerosis and aortic dilation are largely, if not completely, independent of uPAR. In the absence of uPA overexpression, however, uPAR contributes modestly to both atherosclerosis and aortic dilation. Microarray studies identified S100A8 and S100A9 mRNA as the most highly up-regulated transcripts in uPA-overexpressing macrophages; up-regulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also up-regulated in the aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is up-regulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Macrophage microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm in a second animal model that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also reveal uPAR independence of these actions and implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease.Atherosclerosis and aneurysm formation are common cardiovascular diseases that have a significant impact on human health. Atherosclerosis is characterized by accumulation in the inner blood vessel wall of cellular and matrix-rich plaques that cause vessel lumen narrowing and tissue ischemia. Clinical events in patients with atherosclerosis (e.g. heart attacks and strokes) are typically caused by rupture of atherosclerotic plaques with superimposed thrombosis that occludes the vessel lumen (1). In contrast, aneurysms are abnormal expansions of a blood vessel that can lead to complete disruption of the vessel wall, causing sudden death (2). The molecular mechanisms that contribute to plaque growth, plaque rupture, and aneurysm formation are incompletely understood. Elucidation of these mechanisms should enable the development of novel, targeted therapies that improve human health.We and others (3) have hypothesized that the urokinase plasminogen activator (uPA) 6 /plasminoge...

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Myeloid-Related Protein-8/14 Is Critical for the Biological Response to Vascular Injury

Cited by 226 publications

References 42 publications

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

Transcriptome Assessment Reveals a Dominant Role for TLR4 in the Activation of Human Monocytes by the Alarmin MRP8

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

Mechanisms of Urokinase Plasminogen Activator (uPA)-mediated Atherosclerosis

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