Abstract 13: Macrophage Erk5 Activation Induced by Apoptotic Cells and Statins Promotes Efferocytosis and Inhibits Atherosclerosis Formation

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Kyungsun Heo ◽  
Hannah Cushman ◽  
Chang-Hoon Woo ◽  
Masashi Akaike ◽  
Xin Wang ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Cardiac Risk ◽  
Necrotic Core ◽  
High Cholesterol Diet ◽  
Apoptotic Cells ◽  
Phagocytic Capacity ◽  
Fibrous Cap ◽  
Cell Accumulation ◽  
Fibrous Cap Thickness ◽  
Dying Cells

Backgrounds Defective efferocytosis (phagocytic clearance of dying cells) is critically linked to progression of advanced atherosclerotic lesions. Although it has been well known that efferocytosis is processed by molecules including eat-me and find-me signals, it is unclear how efferocytosis becomes defective in advanced lesion. Methods and Results Here, we found that bone marrow-derived macrophages (BMDM) from macrophage-specific ERK5 knockout (ERK5 fl/fl LysM Cre +/- ; ERK5-MKO) mice reduced mRNA and proteins levels of efferocytosis-related signaling molecules such as Mer-tK, C1qa, C1qb, C1qc, Gas6, Mfg-e8, Thbs1, and Anxa1 compared with BMDM from non-transgenic control (NLC) mice. Interestingly, addition of apoptotic cells and pitavastatin activate ERK5 kinase activity and increase opsonins, eat-me and find-me signals, and phagocytic capacity toward apoptotic cells in normal macrophage, but macrophages from ERK5-MKO failed to respond in this manner. ERK5-MKO crossed to LDLR -/- mice and fed a high cholesterol diet for 16-week accelerated atherosclerosis formation with an increased level of apoptotic cell accumulation and necrotic core formation, which was accompanied by a significant reduction in collagen content and fibrous cap thickness. We also found lower levels of expression for Mfg-e8 and Thbs1 in the advanced necrotic core of ERK5-MKO mice compared to NLC mice. Conclusion Our study shows that apoptotic cells and statins-activated ERK5 plays a key role in coordinating the process of efferocytosis. Our results provide a mechanistic understanding of the clinically well-described cardiac risk of acute atherothrombotic events in advanced lesions. 1

scholarly journals Research on the correlation between activating transcription factor 3 expression in the human coronary artery and atherosclerotic plaque stability

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
J. Peng ◽  
C. Y. Le ◽  
B. Xia ◽  
J. W. Wang ◽  
J. J. Liu ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Necrotic Core ◽  
Inflammatory Factors ◽  
Lesion Group ◽  
Control Group ◽  
Atherosclerotic Plaques ◽  
Activating Transcription Factor 3 ◽  
Fibrous Cap ◽  
Fibrous Cap Thickness ◽  
Activating Transcription Factor

Abstract Background Activating transcription factor 3 (ATF3) is an early response gene that is activated in response to atherosclerotic stimulation and may be an important factor in inhibiting the progression of atherosclerosis. In this study, we directly measured the expression of ATF3 and inflammatory factors in human coronary atherosclerotic plaques to examine the relationship between ATF3 expression, inflammation and structural stability in human coronary atherosclerotic plaques. Methods A total of 68 coronary artery specimens were collected from the autopsy group, including 36 cases of sudden death from coronary heart disease (SCD group) and 32 cases of acute death caused by mechanical injury with coronary atherosclerosis (CHD group). Twenty-two patients who had no coronary heart disease were collected as the control group (Con group). The histological structure of the coronary artery was observed under a light microscope after routine HE staining, and the intimal and lesion thicknesses, thickness of the fibrous cap, thickness of necrosis core, degree of lumen stenosis were assessed by image analysis software. Western blotting and immunohistochemistry were used to measure the expression and distribution of ATF3, inflammatory factors (CD45, IL-1β, TNF-α) and matrix metalloproteinase-9 (MMP-9) and vascular cell adhesion molecule 1 (VCAM1) in the coronary artery. The Pearson correlation coefficient was used to analyse the correlation between ATF3 protein expression and inflammatory factors and between ATF3 protein expression and structure-related indexes in the lesion group. Results Compared with those in the control group, the intima and necrotic core in the coronary artery were thickened, the fibrous cap became thin and the degree of vascular stenosis was increased in the lesion group, while the intima and necrotic core became thicker and the fibrous cap became thinner in the SCD group than in the CHD group (P < 0.05). There was no or low expression of ATF3, inflammatory factors, VCAM1 and MMP-9 in the control group, and the expression of inflammatory factors, VCAM1 and MMP-9 in the SCD group was higher than that in CHD group, while the expression of ATF3 in the SCD group was significantly lower than that in CHD group (P < 0.05). In the lesion group, the expression of ATF3 was negatively correlated with intimal and necrotic focus thickness, positively correlated with fibrous cap thickness (P < 0.01), and negatively correlated with inflammatory factors, VCAM1 and MMP-9 (P < 0.01). Conclusions The expression of ATF3 may be related to the progression and stability of atherosclerotic plaques, and may affect the structural stability of atherosclerotic plaques by regulating the inflammatory response, thus participating in the regulation of atherosclerotic progression.

scholarly journals Chemokines as phosphatidylserine-bound ‘find-me’ signals in apoptotic cell clearance

2020 ◽  
Author(s):  
Sergio M. Pontejo ◽  
Philip M. Murphy
Keyword(s):  
Extracellular Vesicles ◽  
Chemokine Receptors ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Anionic Phospholipid ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Plasma ◽  
Signal Activity ◽  
Dying Cells

AbstractChemokines are positively charged cytokines that attract leukocytes by binding to anionic glycosaminoglycans (GAGs) on endothelial cells for efficient presentation to leukocyte G protein-coupled receptors (GPCRs). The atypical chemokine CXCL16 has been reported to also bind the anionic phospholipid phosphatidylserine (PS), but the biological relevance of this interaction remains poorly understood. Here we demonstrate that PS binding is in fact a widely shared property of chemokine superfamily members that, like GAG binding, induces chemokine oligomerization. PS is an essential phospholipid of the inner leaflet of the healthy cell plasma membrane but it is exposed in apoptotic cells to act as an ‘eat-me’ signal that promotes engulfment of dying cells by phagocytes. We found that chemokines can bind PS in pure form as well as in the context of liposomes and on the surface of apoptotic cells and extracellular vesicles released by apoptotic cells, which are known to act as ‘find-me’ signals that chemoattract phagocytes during apoptotic cell clearance. Importantly, we show that GAGs are severely depleted from the surface of apoptotic cells and that extracellular vesicles extracted from apoptotic mouse thymus bind endogenous thymic chemokines and activate cognate chemokine receptors. Together these results indicate that chemokines tethered to surface-exposed PS may be responsible for the chemotactic and find-me signal activity previously attributed to extracellular vesicles, and that PS may substitute for GAGs as the anionic scaffold that regulates chemokine oligomerization and presentation to GPCRs on the GAG-deficient membranes of apoptotic cells and extracellular vesicles. Here, we present a new mechanism by which extracellular vesicles, currently recognized as essential agents for intercellular communication in homeostasis and disease, can transport signaling cytokines.

Utility of high-resolution MR imaging to assess fibrous cap thickness, lipid-rich necrotic core and haemorrhage of carotid atheroma

2009 ◽  
Vol 96 (S1) ◽  
pp. 1-1
Author(s):  
U. Sadat ◽  
V. E. Young ◽  
M. J. Graves ◽  
M. E. Gaunt ◽  
K. Varty ◽  
...  
Keyword(s):  
High Resolution ◽  
Mr Imaging ◽  
Necrotic Core ◽  
Fibrous Cap ◽  
Fibrous Cap Thickness

scholarly journals Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums

2010 ◽  
Vol 207 (9) ◽  
pp. 1807-1817 ◽  
Author(s):  
Kodi S. Ravichandran
Keyword(s):  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
New Information ◽  
Multiple Receptors ◽  
Dying Cells

Everyday we turnover billions of cells. The quick, efficient, and immunologically silent disposal of the dying cells requires a coordinated orchestration of multiple steps, through which phagocytes selectively recognize and engulf apoptotic cells. Recent studies have suggested an important role for soluble mediators released by apoptotic cells that attract phagocytes (“find-me” signals). New information has also emerged on multiple receptors that can recognize phosphatidylserine, the key “eat-me” signal exposed on the surface of apoptotic cells. This perspective discusses recent exciting progress, gaps in our understanding, and the conflicting issues that arise from the newly acquired knowledge.

scholarly journals “Dead Cells Talking”: The Silent Form of Cell Death Is Not so Quiet

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Richard Jäger ◽  
Howard O. Fearnhead
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Apoptotic Cell ◽  
Surrounding Tissue ◽  
Apoptotic Cells ◽  
Cancer Cell Proliferation ◽  
Loss Of Function ◽  
Molecular Events ◽  
Dying Cells

After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.

scholarly journals TNFα inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation

2009 ◽  
Vol 297 (4) ◽  
pp. L586-L595 ◽  
Author(s):  
Valeria M. Borges ◽  
R. William Vandivier ◽  
Kathleen A. McPhillips ◽  
Jennifer A. Kench ◽  
Konosuke Morimoto ◽  
...  
Keyword(s):  
Lung Injury ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Neutrophil Accumulation ◽  
Cell Recruitment ◽  
Apoptotic Cell Clearance ◽  
Persistent Inflammation ◽  
Cell Clearance ◽  
Proinflammatory Responses ◽  
Dying Cells

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNFα blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung. Compared with mice treated with intratracheal TNFα or exogenous apoptotic cells, mice treated with the combination of TNFα plus apoptotic cells demonstrated reduced apoptotic cell clearance from the lungs and increased recruitment of inflammatory leukocytes to the air spaces. Treatment with intratracheal TNFα had no effect on the removal of exogenous apoptotic cells from the lungs of TNFα receptor-1 (p55) and -2 (p75) double mutant mice and no effect on leukocyte recruitment. Bronchoalveolar lavage from mice treated with TNFα plus apoptotic cells contained increased levels of proinflammatory cytokines IL-6, KC, and MCP-1, but exhibited no change in levels of anti-inflammatory cytokines IL-10 and TGF-β. Administration of TNFα plus apoptotic cells during LPS-induced lung injury augmented neutrophil accumulation and proinflammatory cytokine production. These findings suggest that the presence of TNFα in the lung can alter the response of phagocytes to apoptotic cells leading to inflammatory cell recruitment and proinflammatory mediator production.

scholarly journals Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling

2020 ◽  
Author(s):  
Zachary I. Blume ◽  
Jared M. Lambert ◽  
Anna G. Lovel ◽  
Diana M. Mitchell
Keyword(s):  
Real Time ◽  
Apoptotic Cell ◽  
List Type ◽  
Apoptotic Cells ◽  
Real Time Imaging ◽  
Microglial Phagocytosis ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Dying Cells

AbstractBackgroundMicroglia colonize the developing vertebrate central nervous system coincident with detection of developmental apoptosis. Our understanding of apoptosis in intact tissue in relation to microglial clearance of dying cells is largely based on fixed samples, which is limiting given that microglia are highly motile and mobile phagocytes. Here, we used a system of microglial depletion and in vivo real-time imaging in zebrafish to directly address microglial phagocytosis of apoptotic cells during normal retinal development, the relative timing of phagocytosis in relation to apoptotic progression, and the contribution of P2RY12 signaling to this process.ResultsDepletion of microglia resulted in accumulation of numerous apoptotic cells in the retina. Real-time imaging revealed precise timing of microglial engulfment with the progression of apoptosis, and dynamic movement and displacement of engulfed apoptotic cells. Inhibition of P2RY12 signaling delayed microglial clearance of apoptotic cells.ConclusionsMicroglial engulfment of dying cells is coincident with apoptotic progression and requires P2RY12 signaling, indicating that microglial P2RY12 signaling is shared between development and injury response. Our work provides important in vivo insight into the dynamics of apoptotic cell clearance in the developing vertebrate retina and provides a basis to understand microglial phagocytic behavior in health and disease.Bullet PointsLevels and location of developmental apoptosis in the zebrafish retina are elusive due to rapid and efficient clearance by microgliaMicroglial clearance of apoptotic cells is timed with the progression of apoptosis of the engulfed cell so that many cells are cleared in relatively early apoptotic stagesP2RY12 signaling is involved in microglial sensing and clearance of cells undergoing normal developmental apoptosis, indicating shared signals in microglial responses to cell death in both healthy and injured tissueGrant SponsorsNIH NIGMS Grant No. P20 GM103408

The final step in programmed cell death: phagocytes carry apoptotic cells to the grave

2003 ◽  
Vol 39 ◽  
pp. 105-117 ◽  
Author(s):  
Aimee M deCathelineau ◽  
Peter M Henson
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
The Body ◽  
Apoptotic Cells ◽  
Cytokines And Chemokines ◽  
Cell Clearance ◽  
And Function ◽  
Multicellular Organisms ◽  
Dying Cells ◽  
High Degree

As cells undergo apoptosis, they are recognized and removed from the body by phagocytes. This oft-overlooked yet critical final step in the cell-death programme protects tissues from exposure to the toxic contents of dying cells and also serves to prevent further tissue damage by stimulating production of anti-inflammatory cytokines and chemokines. The clearance of apoptotic-cell corpses occurs throughout the lifespan of multicellular organisms and is important for normal development during embryogenesis, the maintenance of normal tissue integrity and function, and the resolution of inflammation. Many of the signal-transduction molecules implicated in the phagocytosis of apoptotic cells appear to have a high degree of evolutionary conservation, and therefore the engulfment of apoptotic cells is likely to represent one of the most primitive forms of phagocytosis. With the realization that the signals that govern apoptotic-cell removal also serve to attenuate inflammation and the immune response, as well as initiate signals for tissue repair and remodelling in response to cell death, the study of apoptotic cell clearance is a field experiencing a dynamic increase in interest and momentum.

scholarly journals Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture

2008 ◽  
Vol 295 (2) ◽  
pp. H717-H727 ◽  
Author(s):  
Jacques Ohayon ◽  
Gérard Finet ◽  
Ahmed M. Gharib ◽  
Daniel A. Herzka ◽  
Philippe Tracqui ◽  
...  
Keyword(s):  
Plaque Rupture ◽  
Necrotic Core ◽  
Plaque Morphology ◽  
Arterial Remodeling ◽  
Plaque Instability ◽  
Fibrous Cap ◽  
Remodeling Index ◽  
Core Thickness ◽  
Fibrous Cap Thickness ◽  
Biomechanical Factors

Fibrous cap thickness is often considered as diagnostic of the degree of plaque instability. Necrotic core area (Corearea) and the arterial remodeling index (Remodindex), on the other hand, are difficult to use as clinical morphological indexes: literature data show a wide dispersion of Corearea thresholds above which plaque becomes unstable. Although histopathology shows a strong correlation between Corearea and Remodindex, it remains unclear how these interact and affect peak cap stress (Capstress), a known predictor of rupture. The aim of this study was to investigate the change in plaque vulnerability as a function of necrotic core size and plaque morphology. Capstress value was calculated on 5,500 idealized atherosclerotic vessel models that had the original feature of mimicking the positive arterial remodeling process described by Glagov. Twenty-four nonruptured plaques acquired by intravascular ultrasound on patients were used to test the performance of the associated idealized morphological models. Taking advantage of the extensive simulations, we investigated the effects of anatomical plaque features on Capstress. It was found that: 1) at the early stages of positive remodeling, lesions were more prone to rupture, which could explain the progression and growth of clinically silent plaques and 2) in addition to cap thickness, necrotic core thickness, rather than area, was critical in determining plaque stability. This study demonstrates that plaque instability is to be viewed not as a consequence of fibrous cap thickness alone but rather as a combination of cap thickness, necrotic core thickness, and the arterial remodeling index.

Sign in / Sign up

Export Citation Format

Share Document