Atherosclerosis – A matter of unresolved inflammation

Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries.     

凋亡和凋亡细胞清除在慢性阻塞性肺疾病发病机制的地位

吸烟是导致慢性阻塞性肺疾病（CODP）气道炎症的主要原因，但戒烟并不能减轻气道炎症，且炎症持续存在，疾病进行性发展和恶化。肺内凋亡细胞清除（胞葬作用：Efferocytosis）缺失可能与其有关，这种现象在COPD发生发展起重要作用。专职和非专职吞噬细胞识别凋亡细胞的过程具有抗炎、抗免疫和抗蛋白水解的作用，并诱导维持肺泡细胞生长因子产生和分泌，其功能缺失将导致凋亡细胞清除降低。一旦凋亡细胞识别缺失，这些作用也随之紊乱，这将对COPD发病机制起重要的作用。凋亡细胞清除缺失这一关键问题如何被发现和如何被控制？至今未有答案。     

丹酚酸B对小鼠动脉粥样硬化病变和巨噬细胞胞葬作用的影响及其机制

探讨丹酚酸B（Sal B）对小鼠动脉粥样硬化病变和氧化型低密度脂蛋白（ox-LDL）诱导的小鼠巨噬细胞胞葬作用的影响,阐明Sal B抗动脉粥样硬化的作用机制。     

The role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis

Accumulating evidence supports the notion that defective phagocytic clearance of dying cells, or defective "efferocytosis," is causally linked to the progression of advanced atherosclerosis. In advanced atherosclerotic lesions, defective efferocytosis leads to post-apoptotic necrosis, expansion of plaque necrotic cores, and susceptibility to atherothrombosis. Both macrophages and DC-like efferocytes are juxtaposed near expanding necrotic cores, where they engage apoptotic cells. In this Viewpoint, we discuss how reduced efferocytosis by macrophages and CD11c(HI) DC-like cells may combine to reduce overall plaque stability and therefore promote susceptibility to acute atherothrombosis.     

The effect of ageing on the resolution of inflammation

Ageing is associated with the development of a low-level, systemic, chronic inflammation known as “inflammaging”. This chronic inflammatory state can contribute to diseases of ageing such as sarcopenia and frailty. The presence of inflammaging suggests a failure of the cell clearance mechanisms that ordinarily aid in the resolution of inflammation after pathogen infiltration or tissue injury. This review aims to explore what is known of how the processes involved in the resolution of inflammation might become defective with age.     

Review: Where is the maternofetal interface?

Ask where the maternofetal interface is and placental biologists will tell you, the syncytiotrophoblast and extravillous cytotrophoblasts. While correct, this is not full extent of the maternofetal interface. Trophoblast debris that is extruded into the maternal blood in all pregnancies expands the maternofetal interface to sites remote from the uterus. Trophoblast debris ranges from multinucleated syncytial nuclear aggregates to subcellular micro- and nano-vesicles. The origins of trophoblast debris are not clear. Some propose trophoblast debris is the end of the life-cycle of the trophoblast and that it results from an apoptosis-like cell death, but this is not universally accepted. Knowing whether trophoblast debris results from an apoptosis-like cell death is important because the nature of cell death that produced trophoblast debris will influence the maternal responses to it. Trophoblast debris is challenging to isolate from maternal blood making it difficult to study. However, by culturing placental explants in Netwells™ we can readily harvest trophoblast debris from beneath the Netwells™ which is very similar to debris that has been isolated from pregnant women. We have found that trophoblast debris from normal placentae shows markers of apoptosis and is phagocytosed by macrophages or endothelial cells, producing a tolerant phenotype in the phagocyte. Whereas, when we culture normal placental explants with factors such as antiphospholipid antibodies (a strong maternal risk factor for preeclampsia), or IL-6 (which is found at increased levels in the sera of preeclamptic women), the death process in the syncytiotrophoblast changes, such that the trophoblast debris becomes more necrotic. Phagocytosis of this necrotic debris leads to activation of endothelial cells. Trophoblast debris greatly expands the maternofetal interface and the nature of that debris is likely to strongly influence the responses of the maternal vascular and immune systems to the debris.     

Efferocytosis as a regulator of macrophage chemokine receptor expression and polarization

Efferocytosis has been suggested to promote macrophage resolution programs that are dependent on motility and emigration, however, few studies have addressed directed migration in resolving macrophages. In this report, we hypothesized that efferocytosis would induce differential chemokine receptor expression. Polarized macrophage populations, including macrophages actively engaged in efferocytosis, were characterized by PCR array and traditional transwell motility assays. We identified specific up‐regulation of chemokine receptor CXCR4 on both mouse and human macrophages and characterized in vivo expression of CXCR4 in a resolving model of murine peritonitis. Using adoptive transfer and AMD3100 blocking, we confirmed a role for CXCR4 in macrophage egress to draining lymphatics. Collectively these data provide an important mechanistic link between efferocytosis and macrophage emigration.     

巨噬细胞的吞噬功能与动脉粥样硬化斑块的稳定性

吞噬性清除凋亡细胞是巨噬细胞的重要生理功能,在动脉粥样硬化斑块的发生、发展和维护斑块的稳定性过程中具有重要作用.本文就巨噬细胞对凋亡细胞识别、摄取和吞噬的分子机制,以及在维护动脉粥样硬化斑块稳定性中的作用作一综述.     

Coronary atherosclerosis:Significance of autophagic armour

Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins.Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer,neurodegeneration,aging and heart failure,a growing body of evidence now reveals a protective role for autophagy in atherosclerosis,mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells.Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.