The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans

Chávez-Sanchéz, Luis; Garza-Reyes, Montserrat Guadalupe; Espinosa-Luna, José Esteban; Chávez-Rueda, Karina; Legorreta-Haquet, María Victoria; Blanco-Favéla, Francisco

doi:10.1016/j.humimm.2014.01.012

Cited by 108 publications

(86 citation statements)

References 34 publications

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“…Similarly, aortic valve thickening is essentially absent in TLR2 KO mice and TLR4 mutant mice fed with a high fat diet, indicating an important role of TLR2/4 in mediating aortic valve lesions. It is interesting that oxLDL deposition is evident in the aortic valve tissue of mice fed with high fat diet because oxLDL has been reported to function as a DAMP (29,40,41). In this regard, we reported that oxLDL induces BMP-2 expression in human coronary artery endothelial cells through TLR2/4 (29).…”

Section: Il-37mentioning

confidence: 75%

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng

Song

Fullerton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Calcific aortic valve disease is a chronic inflammatory process, and aortic valve interstitial cells (AVICs) from diseased aortic valves express greater levels of osteogenic factors in response to proinflammatory stimulation. Here, we report that lower cellular levels of IL-37 in AVICs of diseased human aortic valves likely account for augmented expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) following stimulation of Toll-like receptor (TLR) 2 or 4. Treatment of diseased AVICs with recombinant human IL-37 suppresses the levels of BMP-2 and ALP as well as calcium deposit formation. In mice, aortic valve thickening is observed when exposed to a TLR4 agonist or a high fat diet for a prolonged period; however, mice expressing human IL-37 exhibit significantly lower BMP-2 levels and less aortic valve thickening when subjected to the same regimens. A high fat diet in mice results in oxidized low-density lipoprotein (oxLDL) deposition in aortic valve leaflets. Moreover, the osteogenic responses in human AVICs induced by oxLDL are suppressed by recombinant IL-37. Mechanistically, reduced osteogenic responses to oxLDL in human AVICs are associated with the ability of IL-37 to inhibit NF-κB and ERK1/2. These findings suggest that augmented expression of osteogenic factors in AVICs of diseased aortic valves from humans is at least partly due to a relative IL-37 deficiency. Because recombinant IL-37 suppresses the osteogenic responses in human AVICs and alleviates aortic valve lesions in mice exposed to high fat diet or a proinflammatory stimulus, IL-37 has therapeutic potential for progressive calcific aortic valve disease.Toll-like receptors | inflammation | oxidized low-density lipoprotein | calcification | signal transduction

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Section: Il-37mentioning

confidence: 75%

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Zeng

Song

Fullerton

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In patients with unstable angina, oxLDLs may contribute to monocyte overproduction of some cytokines and above all to that of IL-6 and IL-1β, by upregulating TLR4 expression (Fratta Pasini et al ., 2007). Moreover, activation of the receptors TLR4 and CD36 by oxLDLs in macrophages induces secretion of various cytokines and foam cell formation (Chávez-Sánchez et al ., 2014). It has also been shown that oxLDLs regulate the expression of various inflammatory cytokines via the TLR4/NF-κB pathway in arterial SMCs from wild-type mice.…”

Section: Discussionmentioning

confidence: 99%

Relation between TLR4/NF‐κB signaling pathway activation by 27‐hydroxycholesterol and 4‐hydroxynonenal, and atherosclerotic plaque instability

et al. 2015

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It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll-like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low-density lipoproteins, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high-risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27-OH and HNE were found to enhance cell release of IL-8, IL-1β, and TNF-α and to upregulate matrix metalloproteinase-9 (MMP-9) via TLR4/NF-κB-dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP-9 upregulation, thus enhancing the release of this matrix-degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP-9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF-κB downstream signaling.

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“…oxLDL) with the scavenger receptor CD36, and high-mobility group box 1 protein (HMGB1) contributes to foam cell formation and inflammation, supporting its participation in atherogenesis. 16–20 …”

Section: Emerging Concepts Of the Mechanisms Of Plaque Erosion: Rolesmentioning

confidence: 99%

Mechanisms of erosion of atherosclerotic plaques

Quillard

Franck²,

Mawson³

et al. 2017

Current Opinion in Lipidology

141

118

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Purpose of review This review explores the mechanisms of superficial intimal erosion, a common cause of thrombotic complications of atherosclerosis. Recent findings Human coronary artery atheroma that give rise to thrombosis due to erosion differ diametrically from those associated with fibrous cap rupture. Eroded lesions characteristically contain few inflammatory cells, abundant extracellular matrix, and neutrophil extracellular traps (NETs). Innate immune mechanisms such as engagement of Toll-like receptor 2 (TLR2) on cultured endothelial cells (EC) can impair their viability, attachment, and ability to recover a wound. Hyaluronan fragments may serve as endogenous TLR2 ligands. Mouse experiments demonstrate that flow disturbance in arteries with neointimas tailored to resemble features of human eroded plaques disturbs EC barrier function, impairs EC viability, recruits neutrophils, and provokes EC desquamation, NET formation, and thrombosis in a TLR2-dependent manner. Summary Mechanisms of erosion have received much less attention than those that provoke plaque rupture. Intensive statin treatment changes the characteristic of plaques that render them less susceptible to rupture. Thus, erosion may contribute importantly to the current residual burden of risk. Understanding the mechanisms of erosion may inform the development and deployment of novel therapies to combat the remaining atherothrombotic risk in the statin era.

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The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans

Cited by 108 publications

References 34 publications

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice

Relation between TLR4/NF‐κB signaling pathway activation by 27‐hydroxycholesterol and 4‐hydroxynonenal, and atherosclerotic plaque instability

Mechanisms of erosion of atherosclerotic plaques

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