Activation of CD137 signaling accelerates vascular calcification in vivo and vitro

Chen, Yao; Bangash, Abdul Basit; Song, Juan; Zhong, Wei; Wang, Cuiping; Shao, Chen; Wang, Zhongqun; Yan, Jinchuan

doi:10.1016/j.ijcard.2016.12.174

Cited by 19 publications

(10 citation statements)

References 19 publications

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“…Emerging evidence has revealed that CD137‐CD137L signalling plays an important role in the plaque inflammation during AS development . However, it remains unclear whether EC‐derived exosomes participate in the Th17 cell differentiation, and if so, whether CD137‐CD137L signalling can regulate the immunoregulatory properties in AS development.…”

Section: Discussionmentioning

confidence: 99%

“…Exosomes are a subset of extracellular vesicles (EVs) released by almost all types of cells, and they play a significant role in cellular proliferation, apoptosis, stress response and differentiation in the initial stage and development of AS . In the present study, we investigated exosome‐mediated cell‐to‐cell communication, which induced Th17 cell differentiation and promoted progression of the atherosclerotic plaque.…”

Section: Introductionmentioning

confidence: 99%

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Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Geng

Zang

et al. 2020

J Cellular Molecular Medi

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| 4659 wileyonlinelibrary.com/journal/jcmm 1 | INTRODUC TI ON T helpers 17 (Th17) cells have been identified as a new subset of lymphocytes which are shown to promote atherosclerosis (AS), and their associated cytokines in the pathogenesis of AS appear to be contradictory at first glance. 1-3 Recently, growing attention has been paid to the relative contribution of the local vs. peripheral inflammation to the procession of AS. Here, we focused on the communication between peripheral inflammation and vascular inflammation of Th17 cell differentiation during AS.Exosomes are a subset of extracellular vesicles (EVs) released by almost all types of cells, and they play a significant role in cellular proliferation, apoptosis, stress response and differentiation in the initial stage and development of AS. 4,5 In the present study, we investigated exosome-mediated cell-to-cell communication, which induced Th17 cell differentiation and promoted progression of the atherosclerotic plaque. AbstractThe role of exosomes derived from endothelial cells (ECs) in the progression of atherosclerosis (AS) and inflammation remains largely unexplored. We aimed to investigate whether exosome derived from CD137-modified ECs (CD137-Exo) played a major role in AS and to elucidate the potential mechanism underlying the inflammatory effect. Exosomes derived from mouse brain microvascular ECs treated with agonist anti-CD137 antibody were used to explore the effect of CD137 signalling in AS and inflammation in vitro and vivo. CD137-Exo efficiently induced the progression of AS in ApoE −/− mice. CD137-Exo increased the proportion of Th17 cells both in vitro and vivo. The IL-6 contained in CD137-Exo which is regulated by Akt and NF-КB pathway was verified to activate Th17 cell differentiation. IL-17 increased apoptosis, inhibited cell viability and improved lactate dehydrogenase (LDH) release in ECs subjected to inflammation induced by lipopolysaccharide (LPS). The expression of soluble intercellular adhesion molecule1 (sICAM-1), monocyte chemoattractant protein-1 (MCP-1) and E-selectin in the supernatants of ECs after IL-17 treatment was dramatically increased. CD137-Exo promoted the progression of AS and Th17 cell differentiation via NF-КB pathway mediated IL-6 expression. This finding provided a potential method to prevent local and peripheral inflammation in AS. K E Y W O R D S atherosclerosis, endothelial cells; Th17 cells, exosomes

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Geng

Zang

et al. 2020

J Cellular Molecular Medi

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“…CD137 signaling is an important therapeutic target for development of vascular calcification [ 12 ]. Here, we have demonstrated for the first time that the activation of CD137 signaling could upregulate JNK phosphorylation which subsequently impaired the development of autophagic flux and ultimately leading to the vascular calcification.…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of CD137 reduces atherosclerosis in mice on both chow and high-fat diets [ 11 ]. In addition, we recently showed CD137 signaling contributed to the calcification of atherosclerotic lesions [ 12 ]. However, the underlying mechanisms whereby CD137 signaling affects vascular calcification remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Activation of CD137 Signaling Enhances Vascular Calcification through c-Jun N-Terminal Kinase-Dependent Disruption of Autophagic Flux

Chen

Zhong

et al. 2018

Mediators of Inflammation

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Background Vascular calcification is widespread and clinically significant, contributing to substantial morbidity and mortality. Calcifying vascular cells are partly derived from local vascular smooth muscle cells (VSMCs), which can undergo chondrogenic or osteogenic differentiation under inflammatory environment. Recently, we have found activation of CD137 signaling accelerated vascular calcification. However, the underlying mechanism remains unknown. This study aims to identify key mediators involved in CD137 signaling-induced vascular calcification in vivo and in vitro. Methods Autophagy flux was measured through mRFP-GFP-LC3 adenovirus and transmission electron microscopy. Von Kossa assay and alkaline phosphatase (ALP) activity were used to observe calcification in vivo and in vitro, respectively. Autophagosome-containing vesicles were collected and identified by flow cytometry and Western blot. Autophagy or calcification-associated targets were measured by Western blot, quantitative real-time PCR, and immunohistochemistry. Results Treatment with the agonist-CD137 displayed c-Jun N-terminal kinase- (JNK-) dependent increase in the expression of various markers of autophagy and the number of autophagosomes relative to the control group. Autophagy flux experiments suggested that agonist-CD137 blocked the fusion of autophagosomes with lysosomes in cultured VSMCs. Calcium deposition, ALP activity, and the expression of calcification-associated proteins also increased in agonist-CD137 group compared with anti-CD137 group, which could be recovered by autophagy stimulator rapamycin. Autophagosome-containing vesicles collected from agonist-CD137 VSMCs supernatant promoted VSMC calcification. Conclusion The present study identified a new pathway in which CD137 promotes VSMC calcification through the activation of JNK signaling, subsequently leading to the disruption of autophagic flux, which is responsible for CD137-induced acceleration of vascular calcification.

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“…To examine the expression of IL-1β, MH-S cells were pretreated with lipopolysaccharide (LPS, 25 ng/mL, Sigma-Aldrich Chemical Company) for 3 h (Figure 4 J). Agonist 4-1BB mAb (10 µg/mL; cat: MAB9371, R&D Systems, Minneapolis, MN, USA) ( 19 ) was used to detect the effect of 4-1BB signaling on macrophages 2 h before CS exposure. Isotype IgG (10 µg/mL, Sino Biological Inc.) was used as a control.…”

Section: Methodsmentioning

confidence: 99%

4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice

et al. 2018

Front. Immunol.

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Silicosis is caused by exposure to crystalline silica (CS). We have previously shown that blocking 4-1BB signaling attenuated CS-induced inflammation and pulmonary fibrosis. However, the cells that express 4-1BB, which plays a vital role in promoting fibrosis, are still unknown. In this study, we demonstrated that the expression of 4-1BB is elevated in alveolar macrophages (AMs) in the lungs of CS-injured mice. CS exposure also markedly enhanced the expression of 4-1BB in macrophage-like, MH-S cells. In these cells, activation of the 4-1BB signaling with an agonist antibody led to upregulated secretion of pro-fibrotic mediators. Consistently, blocking 4-1BB downstream signaling or genetic deletion of 4-1BB alleviated pro-fibrotic responses in vitro, while treatment with a 4-1BB fusion protein promoted pro-fibrotic responses. In vivo experiments showed that blocking 4-1BB signaling decreased the expressions of pro-fibrotic mediators and fibrosis. These data suggest that 4-1BB signaling plays an important role in promoting AMs-mediated pro-fibrotic responses and pulmonary fibrosis. Our findings may provide a potential molecular target to reduce CS-induced fibrotic responses in occupational lung disease.

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Activation of CD137 signaling accelerates vascular calcification in vivo and vitro

Cited by 19 publications

References 19 publications

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Exosome derived from CD137‐modified endothelial cells regulates the Th17 responses in atherosclerosis

Activation of CD137 Signaling Enhances Vascular Calcification through c-Jun N-Terminal Kinase-Dependent Disruption of Autophagic Flux

4-1BB Signaling Promotes Alveolar Macrophages-Mediated Pro-Fibrotic Responses and Crystalline Silica-Induced Pulmonary Fibrosis in Mice

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