Engulfment of apoptotic cells by microvascular endothelial cells induces proinflammatory responses

Abstract

IntroductionApoptosis is essential to maintain homeostasis in multicellular organisms and apoptotic cells are rapidly and effectively cleared by professional phagocytes before they undergo secondary necrosis and release their noxious cytoplasmic content into the environment. 1 Ineffective clearance of apoptotic cells contributes to disease pathogenesis. 2,3 This may be true especially for autoimmune diseases such as systemic lupus erythematosus (SLE) because apoptotic cells are thought to be a potential source of autoantigens and disturbed clearance of apoptotic corpses may initiate and drive autoimmunity. [4][5][6] This concept of acquired autoimmunity has also been confirmed in several animal models that showed disturbed engulfment of apoptotic cells. [7][8][9][10] Vascular endothelial cells (ECs) serve as a crucial barrier between tissues and the circulation. They secrete a variety of substances, regulate coagulation, and participate in the immune response. 11 Under physiologic conditions circulating ECs (CECs) are almost not traceable, whereas in a variety of vascular diseases such as myocardial infarction, small-vessel vasculitis, transplantation, or cancer high numbers of CECs are detectable in the peripheral circulation. [12][13][14][15][16][17] Consequentially, accumulation of CECs may affect the homeostasis of the vessel wall by interfering with the EC layer both in the vicinity of endothelial lesions or even distant from the site of injury.Clearance of dying cells or cellular debris has been mostly ascribed to professional phagocytes, for example, antigenpresenting macrophages, neutrophils, or dendritic cells, but it is conceivable that other cell types such as epithelial cells or ECs may also partake in this process. 18,19 ECs are not professional phagocytes although specific subpopulations, such as liver ECs or cells from high endothelial venules, are able to phagocytose apoptotic cells. 20,21 Phagocytosis of circulating endothelial debris by healthy endothelium thus appears to be an intriguing concept.The role of endothelial-or platelet-derived microparticles in the circulation is the subject of several recently published studies but few, if any, data, shed light on the impact of apoptotic endothelial corpses on the adjacent endothelium. [22][23][24][25][26][27][28][29][30][31] The aim of the present study was to establish an in vitro model to study the interaction of apoptotic or necrotic ECs with a healthy EC layer. We here demonstrate that microvascular ECs, when exposed to apoptotic cells, react with the release of proinflammatory chemotactic cytokines and that this response triggers enhanced adhesion of primary neutrophils and macrophages. Patients, materials, and methodsThe study was approved by the Hannover Medical School Ethics Committee and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients included in this study. EC cultureHuman umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords by exposure of the vein...

Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells

“…HUVECs from ScienCell used up to passage 4 21 were cultured in EC medium containing 5% FBS, 1% EC growth supplement, and antibiotics.…”

Markers of Vascular Damage and Repair

“…Support for these findings came from other studies demonstrating the phagocytic capability of endothelial cells 54 . We could also show that endothelial cells exposed to apoptotic and necrotic cells exhibit enhanced adhesion properties for leukocytes and that isolated CEC from patients with vasculitis aggravated these effects further 53 . These effects on binding properties could be explained in part by release of IL-8 and MCP1, which serve as chemo-attractants.…”

“…Disturbed clearance of apoptotic cells may play a role in systemic lupus erythematosus 52 . Interestingly, apoptotic and necrotic endothelial cells and their fragments are rapidly internalized by healthy endothelium 53 . Support for these findings came from other studies demonstrating the phagocytic capability of endothelial cells 54 .…”

DNA chimerism and its consequences after allogeneic hematopoietic cell transplantation

“…25,26 A critical role of DNA trafficking between cells has been also suggested in different clinical settings as in inflammation, in cancer and after organ transplantation. 17,18,27,28 Most recently, Ehnfors et al 29 used a rat-to-SCID mouse tumor xenotransplant system and showed that tumor DNA can be transferred in vivo by detecting rat and mouse fusion chromosomes in mouse tumor stromal cells. Such an approach could be also applicable in a hematopoietic cell xenotransplantation system (e.g.…”

“…Apoptosis is a well-recognized source of DNA in several clinical settings, such as cancer, extensive burning, GvHD and transplantation. [15][16][17][18][19][20] Donor cells undergoing apoptosis release donor-DNA packaged into apoptotic bodies. 21 Although foreign DNA is normally cleared up, 22 the fate of the large amount of released donorderived genetic material in the transplant recipient is unknown.…”