A Novel Mechanism of γ/δ T-Lymphocyte and Endothelial Activation by Shear Stress

Fu, Yi; Hou, Yingjian; Fu, Cheng; Gu, Mingxia; Li, Chenghong; Kong, Wei; Wang, Xian; Shyy, John Y.‐J.; Zhu, Yi

doi:10.1161/circresaha.110.230151

Cited by 43 publications

(38 citation statements)

References 35 publications

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“…Because OS increases the cholesterol content of EC membranes, the cholesterol-enriched lipid rafts may thus sequester integrin α5 to allow for its sustained activation. This notion is supported by our previous observation that Cav1 and the F-actin-based cytoskeleton are involved in protein translocation into lipid rafts (21,22). Indeed, results in Fig.…”

Section: Discussionsupporting

confidence: 83%

“…We have previously reported that shear stress changes membrane fluidity temporally and spatially (25). Specifically, OS increases the cholesterol content in EC membranes, which results in decreased membrane fluidity (21). Such alterations of biophysical properties would affect the structure and function of membrane-associated proteins, especially those found in lipid rafts, such as integrin α5.…”

Section: Discussionmentioning

confidence: 99%

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Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Sun

et al. 2016

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

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Local flow patterns determine the uneven distribution of atherosclerotic lesions. Membrane lipid rafts and integrins are crucial for shear stress-regulated endothelial function. In this study, we investigate the role of lipid rafts and integrin α5 in regulating the inflammatory response in endothelial cells (ECs) under atheroprone versus atheroprotective flow. Lipid raft proteins were isolated from ECs exposed to oscillatory shear stress (OS) or pulsatile shear stress, and then analyzed by quantitative proteomics. Among 396 proteins redistributed in lipid rafts, integrin α5 was the most significantly elevated in lipid rafts under OS. In addition, OS increased the level of activated integrin α5 in lipid rafts through the regulation of membrane cholesterol and fluidity. Disruption of F-actin-based cytoskeleton and knockdown of caveolin-1 prevented the OS-induced integrin α5 translocation and activation. In vivo, integrin α5 activation and EC dysfunction were observed in the atheroprone areas of low-density lipoprotein receptor-deficient (Ldlr −/− ) mice, and knockdown of integrin α5 markedly attenuated EC dysfunction in partially ligated carotid arteries. Consistent with these findings, mice with haploinsufficency of integrin α5 exhibited a reduction of atherosclerotic lesions in the regions under atheroprone flow. The present study has revealed an integrin-and membrane lipid raft-dependent mechanotransduction mechanism by which atheroprone flow causes endothelial dysfunction.integrin | lipid rafts | shear stress | proteomics | endothelial dysfunction S hear stress imposed on vascular endothelial cells (ECs) influences vascular phenotype and function. Atherosclerosis preferentially develops at branches and curvatures in the arterial tree where flow is disturbed. In contrast, pulsatile shear stress (PS) in the straight parts of the arteries is atheroprotective (1). At the cellular and molecular levels, disturbed flow pattern increases, while PS inhibits, the inflammatory response in ECs, including the expression of intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), and interleukin 1β (IL-1β) (2). We found that integrins in ECs are shear stress-sensitive (3). Many subsequent studies demonstrated that integrin activation is essential for transmitting mechanical stimuli to intracellular biochemical pathways (4-6). Additionally, mounting evidence indicates that lipid raft microdomains, membrane receptors, cytoskeletal proteins, and extracellular matrices are linked to integrin activation in the context of mechanotransduction (7-11). However, the key mechanism underlying the differential effects of atheroprone versus atheroprotective flows in activating integrins that in turn induces inflammatory response in ECs remains to be elucidated.Lipid rafts are membrane microdomains that are enriched in cholesterol, sphingolipids, and a variety of signaling molecules, which function as cellular signaling platforms. These microdomains are more ordered and tightly packed than the surrounding membran...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Sun

et al. 2016

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

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“…Literally along the same vein, it was later observed that shear stress experienced by endothelial cells also led to the translocation of the ATP synthase b chain to the cell surface which resulted in the binding and activation of Vc9Vd2 T cells. 75 Reminiscent of the previous findings with F1-ATPase, the response of cd T cells to endothelial cells expressing ATP synthase b was significantly potentiated by the coincident accumulation of cholesterol in the cell membrane, and this interaction led to the secretion of inflammatory cytokines by cd T cells and upregulation of vascular cell adhesion molecules on endothelial cells. 75 This phenomenon was taken to suggest that endothelial dysfunction, characterized by the disturbed flow created by shear stress, and hypercholesterolemia work synergistically to activate cd T cells and the endothelium 75 -providing a novel mechanism contributing to cardiovascular pathology.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 61%

“…75 Reminiscent of the previous findings with F1-ATPase, the response of cd T cells to endothelial cells expressing ATP synthase b was significantly potentiated by the coincident accumulation of cholesterol in the cell membrane, and this interaction led to the secretion of inflammatory cytokines by cd T cells and upregulation of vascular cell adhesion molecules on endothelial cells. 75 This phenomenon was taken to suggest that endothelial dysfunction, characterized by the disturbed flow created by shear stress, and hypercholesterolemia work synergistically to activate cd T cells and the endothelium 75 -providing a novel mechanism contributing to cardiovascular pathology. In an attempt to reconcile the established reactivity of Vc9Vd2 T cells to non-peptidic pAgs and these new observations of alternative stress-induced ligands, experiments were carried out to demonstrate that ATP synthase can also potentially bind to pAgs, and it was concluded that it seemingly has the appropriate features to function as a possible pAg presenting molecule for Vc9Vd2 T cells.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 61%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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“…Human umbilical vein endothelial cells were isolated and cultured as previously described (13). UM-SCC-22B (22B) human head and neck squamous carcinoma cells and A549 human non-small cell lung cancer cells were grown in high glucose Dulbecco modified Eagle medium supplemented with 10% fetal bovine serum at 37°C in humidified atmosphere containing 5% CO 2 .…”

Section: Cell Culture and Animal Modelsmentioning

confidence: 99%

Early Assessment of Tumor Response to Gefitinib Treatment by Noninvasive Optical Imaging of Tumor Vascular Endothelial Growth Factor Expression in Animal Models

et al. 2014

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Epidermal growth factor receptor (EGFR) expression is upregulated in many types of tumors, and the EGFR tyrosine kinase inhibitor gefitinib has high potential as an anticancer drug. However, accumulating clinical evidence has indicated that only a subset of patients benefit from gefitinib treatment. This study aimed to determine whether optical imaging of vascular endothelial growth factor (VEGF) expression can be an early biomarker for tumor response to gefitinib therapy. Methods: A VEGF-targeting fluorescent probe Dye-BevF(ab′) 2 was prepared and tested in vivo. Longitudinal optical imaging studies using Dye-BevF(ab′) 2 were performed in both 22B (gefitinib-resistant) and A549 (gefitinib-responsive) tumor models at different times (days 0, 2, and 5) before and after gefitinib treatment. The imaging results were validated by ex vivo immunofluorescence staining and enzymelinked immunosorbent assay. Results: Dye-BevF(ab′) 2 exhibited high specificity for VEGF in vivo. There was no significant change in the Dye-BevF(ab′) 2 uptake in gefitinib-treated 22B tumors, compared with the control group. In contrast, the A549 tumor uptake of DyeBevF(ab′) 2 in the gefitinib-treated group was significantly lower on days 2 and 5 than that in the control group and at the baseline. An in vivo gefitinib treatment study confirmed that 22B tumors were gefitinibresistant, whereas A549 tumors were gefitinib-responsive. Immunofluorescence staining and enzyme-linked immunosorbent assay confirmed that changes in the Dye-BevF(ab′) 2 uptake were correlated with VEGF expression levels in tumors. Conclusion: Optical imaging of VEGF expression with Dye-BevF(ab′) 2 can be used for the early assessment of tumor response to gefitinib therapy. This approach may also be valuable for preclinical high-throughput screening of novel antiangiogenic drugs.

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A Novel Mechanism of γ/δ T-Lymphocyte and Endothelial Activation by Shear Stress

Cited by 43 publications

References 35 publications

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Activation of integrin α5 mediated by flow requires its translocation to membrane lipid rafts in vascular endothelial cells

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Early Assessment of Tumor Response to Gefitinib Treatment by Noninvasive Optical Imaging of Tumor Vascular Endothelial Growth Factor Expression in Animal Models

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