Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis

Yurdagul, Arif; Doran, Amanda C.; Cai, Bolin; Fredman, Gabrielle; Tabas, Ira

doi:10.3389/fcvm.2017.00086

Cited by 220 publications

(200 citation statements)

References 119 publications

(127 reference statements)

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“…Besides PTX3, our study demonstrated that other molecules with anti-in ammatory properties are present in the male EC secretome. Speci cally, it also contains signi cant levels of calreticulin, one of the most characterized eat-me signals [58,59]. In accordance with our data in PTX3-silenced male ECs, decreased levels of calreticulin have been associated to an impaired efferocytosis [60].…”

Section: Discussionsupporting

confidence: 90%

Sex-Dependent Differences in the Secretome of Human Endothelial Cells

Cattaneo

Banfi

Brioschi

et al. 2020

Preprint

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Background: Cellular sex has been rarely considered as a biological variable in preclinical research, even when the pathogenesis of diseases with predictable sex differences is studied. In this perspective, proteomics, and ‘omics approaches in general, can provide powerful tools to obtain comprehensive cellular maps, thus favoring the discovery of still unknown sex-biased physio-pathological mechanisms.Methods: We performed proteomic and gene ontology (GO) analyses of secretome from human serum-deprived male and female endothelial cells (ECs) followed by ELISA validation. Apoptosis was detected by FACS and western blot techniques, and efferocytosis through the ability of the macrophage cell line RAW-264.7 to engulf apoptotic ECs. Protein expression and silencing efficacy were assessed by RT-qPCR. Results: Proteomic and GO analyses of the secretome from starved human male and female ECs demonstrated a significant enrichment in proteins related to cellular responses to stress and to the regulation of apoptosis in the secretome of male ECs. Accordingly, a higher percentage of male ECs underwent apoptosis in response to serum deprivation in comparison to female ECs. Among the secreted proteins, we reliably found higher levels of PTX3 in the male EC secretome. The silencing of PTX3 proved that male ECs were dependent on its expression to properly carry out the efferocytotic process. At variance, female EC efferocytosis was independent of PTX3 expression. Conclusions: Our results demonstrated that serum-starved male and female ECs possess different secretory phenotypes that might take part in the sex-biased response to cellular stress. We identified PTX3 as a crucial player in the male-specific endothelial response to an apoptotic trigger. This novel and sex-related role for secreted proteins, and mainly for PTX3, may open the way to the discovery of still unknown sex-specific mechanisms and pharmacological targets for the prevention and treatment of endothelial dysfunction at the onset of atherosclerosis and cardiovascular disease.

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Section: Discussionsupporting

confidence: 90%

Sex-Dependent Differences in the Secretome of Human Endothelial Cells

Cattaneo

Banfi

Brioschi

et al. 2020

Preprint

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“…Widespread phagocytosis of modified lipoproteins and apoptotic cells by macrophages plays a complex role in the pathogenesis of atherosclerosis. This process can have either pro‐ and anti‐atherogenic effects through context‐dependent activation or resolution of inflammation, respectively 42,43 . To assess the effect of L13a deficiency on the phagocytic activity of macrophages, we performed phagocytosis assays with BMDM using Zymosan as a substrate.…”

Section: Resultsmentioning

confidence: 99%

High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis

et al. 2020

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Previously, we identified a mechanism of inflammation control directed by ribosomal protein L13a and "GAIT" (Gamma Activated Inhibitor of Translation) elements in target mRNAs and showed that its elimination in myeloid cell-specific L13a knockout mice (L13a KO) increased atherosclerosis susceptibility and severity. Here, we investigated the mechanistic basis of this endogenous defense against atherosclerosis. We compared molecular and cellular aspects of atherosclerosis in high-fat diet (HFD)-fed L13a KO and intact (control) mice. HFD treatment of control mice induced release of L13a from 60S ribosome, formation of RNA-binding complex, and subsequent GAIT element-mediated translational silencing. Atherosclerotic plaques from HFD-treated KO mice showed increased infiltration of M1 type inflammatory macrophages. Macrophages from KO mice showed increased phagocytic activity and elevated expression of LDL receptor and pro-inflammatory mediators. NanoString analysis of the plaques from KO mice showed upregulation of a number of mRNAs encoding inflammatory proteins. Bioinformatics analysis suggests the presence of the potential GAIT elements in the 3′UTRs of several of these mRNAs. Macrophage induces L13a/GAIT-dependent translational silencing of inflammatory genes in response to HFD as an endogenous defense against atherosclerosis in ApoE −/− model. K E Y W O R D S atherosclerosis, GAIT, inflammation, L13a, translational control

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“…Specific populations of innate immune effector macrophages take up apoptotic cells in particular tissues, known as efferocytosis, which prevents apoptotic cells from being necrotic or pro-inflammatory [138]. The impaired ability of macrophage efferocytosis would enhance atherogenesis [139][140][141] and atherosclerotic plaque instability [142][143][144]. For example, interferon regulatory factor 5 (IRF5) transcription factor enhances vulnerable plaque formation in hyperlipidemic apolipoprotein E-deficient (ApoE −/− ) mice through the induction of pro-inflammatory CD11c + macrophages within atherosclerotic lesions and increasing the expansion of the necrotic core by inhibiting macrophage efferocytosis [142].…”

Section: Macrophagesmentioning

confidence: 99%

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Song

2020

Cells

127

115

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Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

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Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis

Cited by 220 publications

References 119 publications

Sex-Dependent Differences in the Secretome of Human Endothelial Cells

Sex-Dependent Differences in the Secretome of Human Endothelial Cells

High‐fat diet‐induced GAIT element‐mediated translational silencing of mRNAs encoding inflammatory proteins in macrophage protects against atherosclerosis

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

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