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Clearance of apoptotic cells

Magdalena Paolino, Josef M Penninger
The TAM receptor protein tyrosine kinases-Tyro3, Axl, and Mer-are essential regulators of immune homeostasis. Guided by their cognate ligands Growth arrest-specific gene 6 (Gas6) and Protein S (Pros1), these receptors ensure the resolution of inflammation by dampening the activation of innate cells as well as by restoring tissue function through promotion of tissue repair and clearance of apoptotic cells. Their central role as negative immune regulators is highlighted by the fact that deregulation of TAM signaling has been linked to the pathogenesis of autoimmune, inflammatory, and infectious diseases...
October 21, 2016: Cancers
Xuehua Piao, Soh Yamazaki, Sachiko Komazawa-Sakon, Sanae Miyake, Osamu Nakabayashi, Takeyuki Kurosawa, Tetsuo Mikami, Minoru Tanaka, Nico Van Rooijen, Masaki Ohmuraya, Akira Oikawa, Yuko Kojima, Soichiro Kakuta, Yasuo Uchiyama, Masato Tanaka, Hiroyasu Nakano
: Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (Cflar(Hep-low) ) mice. Cellular FLICE-inhibitory protein (cFLIP) expression was downregulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor-induced apoptosis...
October 22, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Ding-Jun Hao, Cuicui Liu, Lingling Zhang, Bo Chen, Qian Zhang, Rui Zhang, Jing An, Jingjing Zhao, Mingmei Wu, Yi Wang, Alfred Simental, Baorong He, Hao Yang
The gradual deterioration following central nervous system (CNS) injuries or neurodegenerative disorders is usually accompanied by infiltration of degenerated and apoptotic neural tissue debris. A rapid and efficient clearance of these deteriorated cell products is of pivotal importance in creating a permissive environment for regeneration of those damaged neurons. Our recent report revealed that the phagocytic activity of olfactory ensheathing cells (OECs) can make a substantial contribution to neuronal growth in such a hostile environment...
October 14, 2016: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Pranjali Dalvi, Himanshu Sharma, Mahendran Chinnappan, Miles Sanderson, Julie Allen, Ruoxi Zeng, Augustine Choi, Amy O'Brien-Ladner, Navneet K Dhillon
Intravenous drug use is one of the major risk factors for HIV-infection in HIV-related pulmonary arterial hypertension patients. We previously demonstrated exaggerated pulmonary vascular remodeling with enhanced apoptosis followed by increased proliferation of pulmonary endothelial cells on simultaneous exposure to both opioids and HIV protein(s). Here we hypothesize that the exacerbation of autophagy may be involved in the switching of endothelial cells from an early apoptotic state to later hyper-proliferative state...
October 10, 2016: Autophagy
Uriel Trahtemberg, Amir Grau, Adi Tabib, Mizhir Atallah, Alon Krispin, Dror Mevorach
Human monocyte-derived dendritic cells (mdDCs) are versatile cells that are used widely for research and experimental therapies. Although different culture conditions can affect their characteristics, there are no known subpopulations. Since monocytes differentiate into dendritic cells (DCs) in a variety of tissues and contexts, we asked whether they can give rise to different subpopulations. In this work we set out to characterize two human mdDC subpopulations that we identified and termed small (DC-S) and large (DC-L)...
2016: PloS One
Enrique A Daza, Santosh K Misra, Aaron S Schwartz-Duval, Ayako Ohoka, Callie Miller, Dipanjan Pan
The use of cesium chloride (CsCl) for cancer therapy ("high pH therapy") has been theorized to produce anticancer properties by raising intracellular pH to induce apoptosis. Although considered as "alternative medicine", little scientific evidence supports this theory. Alternatively, cells have no cesium ion (Cs(+)) mediated channels for clearance. Thus, such unstable electrochemical distributions have the severe potential to disrupt electrochemical dependent cellular processes, such as glucose cotransporters...
October 3, 2016: ACS Applied Materials & Interfaces
Pei Zhou, Yu-Zhen Tan, Hai-Jie Wang, Ting Li, Tao He, Ying Yu, Jian Zhang, Dan Zhang
Clearance of the apoptotic cells by phagocytes plays pivotal roles in maintenance of tissue homeostasis, promotion of immunological tolerance and anti-inflammatory response. Recent studies show that autophagy is involved in phagocytosis of the apoptotic cells. However, contribution of autophagy to phagocytosis of the apoptotic cells by macrophages is not clearly defined. Here, we assessed cytoprotective effect of autophagy on clearance of the apoptotic cells. Apoptosis of murine splenic lymphocytes and human T-cell leukemia cells was induced with cyclophosphamide...
September 20, 2016: Experimental Cell Research
J G Yeo, J Leong, T Arkachaisri, Y Cai, B H D Teo, J H T Tan, L Das, J Lu
Effective clearance of apoptotic cells by phagocytes prevents the release of intracellular alarmins and manifestation of autoimmunity. This prompt efferocytosis is complemented by intracellular proteolytic degradation that occurs within the apoptotic cells and in the efferosome of the phagocytes. Although the role of extracellular proteases in apoptotic cells clearance is unknown, the strong association of congenital C1s deficiency with Systemic Lupus Erythematosus highlights the protective nature that this extracellular protease has against autoimmunity...
2016: Cell Death Discovery
J Moritz Kaths, Jun Yu Cen, Yi Min Chun, Juan Echeverri, Ivan Linares, Sujani Ganesh, Paul Yip, Rohan John, Darius Bagli, Istvan Mucsi, Anand Ghanekar, David Grant, Lisa A Robinson, Markus Selzner
Hypothermic preservation is known to cause renal graft injury, especially in donation after circulatory death (DCD) kidney transplantation. We investigated the impact of cold storage (SCS) vs. short periods of normothermic ex vivo kidney perfusion (NEVKP) after SCS vs. prolonged, continuous NEVKP with near avoidance of SCS on kidney function after transplantation. Following 30 minutes of warm ischemia, kidneys were removed from 30kg Yorkshire pigs and preserved for 16h with: A) 16h SCS, B) 15h SCS + 1h NEVKP, C) 8h SCS + 8h NEVKP, D) 16h NEVKP...
September 20, 2016: American Journal of Transplantation
Georgia K Atkin-Smith, Ivan K H Poon
The disassembly of an apoptotic cell into subcellular fragments, termed apoptotic bodies (ApoBDs), is a hallmark of apoptosis. Although the generation of ApoBDs is generally understood as being stochastic, it is becoming increasingly clear that ApoBD formation is a highly regulated process involving distinct morphological steps and molecular factors. Functionally, ApoBDs could facilitate the efficient clearance of apoptotic material by surrounding phagocytes as well as mediate the transfer of biomolecules including microRNAs and proteins between cells to aid in intercellular communications...
September 16, 2016: Trends in Cell Biology
Michael Eschbaumer, Carolina Stenfeldt, George R Smoliga, Juan M Pacheco, Luis L Rodriguez, Robert W Li, James Zhu, Jonathan Arzt
In order to investigate the mechanisms of persistent foot-and-mouth disease virus (FMDV) infection in cattle, transcriptome alterations associated with the FMDV carrier state were characterized using a bovine whole-transcriptome microarray. Eighteen cattle (8 vaccinated with a recombinant FMDV A vaccine, 10 non-vaccinated) were challenged with FMDV A24 Cruzeiro, and the gene expression profiles of nasopharyngeal tissues collected between 21 and 35 days after challenge were compared between 11 persistently infected carriers and 7 non-carriers...
2016: PloS One
Bangwei Luo, Fuyu Han, Kai Xu, Jinsong Wang, Zongwei Liu, Zigang Shen, Jia Li, Yu Liu, Man Jiang, Zhi-Yuan Zhang, Zhiren Zhang
UNLABELLED: Experimental autoimmune neuritis (EAN) is the animal model of human acute inflammatory demyelinating polyradiculoneuropathies (AIDP), an auto-immune inflammatory demyelination disease of the peripheral nervous system (PNS) and the world's leading cause of acute autoimmune neuromuscular paralysis. EAN and AIDP are characterized by self-limitation with spontaneous recovery; however, endogenous pathways that regulate inflammation resolution in EAN and AIDP remain elusive. A pathway of endogenous mediators, especially resolvins and clearance of apoptotic cells, may be involved...
September 14, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Naiara N Dejani, Stephanie L Brandt, Annie Piñeros, Nicole L Glosson-Byers, Sue Wang, Young Min Son, Alexandra I Medeiros, C Henrique Serezani
Diabetics are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection is dependent on dendritic cell (DC)-induced Th17-mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IAC) drive prostaglandin E2 (PGE2) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes (LNs) and impairs Th17 differentiation that accounts for poor skin host defense in diabetic mice...
September 7, 2016: Diabetes
Kathrin Sinningen, Sylvia Thiele, Lorenz C Hofbauer, Martina Rauner
Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that is abundantly expressed in various tissues and has a pivotal role in the phagocytic clearance of apoptotic cells. However, MFG-E8 has also gained significant attention because of its wide range of functions in autoimmunity, inflammation and tissue homeostasis. More recently, MFG-E8 has been identified as a critical regulator of bone homeostasis, being expressed in both, osteoblasts and osteoclasts. In addition, it was shown that MFG-E8 fulfils an active role in modulating inflammatory processes, suggesting an anti-inflammatory role of MFG-E8 and proposing it as a novel therapeutic target for inflammatory diseases...
2016: BoneKEy Reports
Zhen Bian, Lei Shi, Ya-Lan Guo, Zhiyuan Lv, Cong Tang, Shuo Niu, Alexandra Tremblay, Mahathi Venkataramani, Courtney Culpepper, Limin Li, Zhen Zhou, Ahmed Mansour, Yongliang Zhang, Andrew Gewirtz, Koby Kidder, Ke Zen, Yuan Liu
Rapid clearance of adoptively transferred Cd47-null (Cd47(-/-)) cells in congeneic WT mice suggests a critical self-recognition mechanism, in which CD47 is the ubiquitous marker of self, and its interaction with macrophage signal regulatory protein α (SIRPα) triggers inhibitory signaling through SIRPα cytoplasmic immunoreceptor tyrosine-based inhibition motifs and tyrosine phosphatase SHP-1/2. However, instead of displaying self-destruction phenotypes, Cd47(-/-) mice manifest no, or only mild, macrophage phagocytosis toward self-cells except under the nonobese diabetic background...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Derek Dc Ireland, Cecilia Tami, Joao Pedras-Vasconcelos, Daniela Verthelyi
Neonates are at increased risk of viral encephalopathies that can result in neurological dysfunction, seizures, permanent disability and even death. The neurological damage results from the combined effect of the virus and the immune response it elicits, thus finding tools to facilitate viral clearance from central nervous system (CNS) while minimizing neuron damage remains a critical challenge. Neonatal mice inoculated intraperitoneally with Tacaribe virus (TCRV) develop seizures, hindlimb paralysis and death within 15 days of inoculation...
August 29, 2016: Cellular & Molecular Immunology
Aaron M Fond, Kodi S Ravichandran
The efficient clearance of apoptotic cells is an evolutionarily conserved process crucial for homeostasis in multicellular organisms. The clearance involves a series of steps that ultimately facilitates the recognition of the apoptotic cell by the phagocytes and the subsequent uptake and processing of the corpse. These steps include the phagocyte sensing of "find-me" signals released by the apoptotic cell, recognizing "eat-me" signals displayed on the apoptotic cell surface, and then intracellular signaling within the phagocyte to mediate phagocytic cup formation around the corpse and corpse internalization, and the processing of the ingested contents...
2016: Advances in Experimental Medicine and Biology
Mallary C Greenlee-Wacker
The engulfment of apoptotic cells by phagocytes, a process referred to as efferocytosis, is essential for maintenance of normal tissue homeostasis and a prerequisite for the resolution of inflammation. Neutrophils are the predominant circulating white blood cell in humans, and contain an arsenal of toxic substances that kill and degrade microbes. Neutrophils are short-lived and spontaneously die by apoptosis. This review will highlight how the engulfment of apoptotic neutrophils by human phagocytes occurs, how heterogeneity of phagocyte populations influences efferocytosis signaling, and downstream consequences of efferocytosis...
September 2016: Immunological Reviews
Tracy L Meehan, Sandy B Serizier, Sarah E Kleinsorge, Kimberly McCall
Programmed cell death (PCD) is essential for health and development. Generally, the last step of PCD is clearance, or engulfment, by phagocytes. Engulfment can be broken down into five basic steps: attraction of the phagocyte, recognition of the dying cell, internalization, phagosome maturation, and acidification of the engulfed material. The Drosophila melanogaster ovary serves as an excellent model to study diverse types of PCD and engulfment by epithelial cells. Here, we describe several methods to detect and analyze multiple steps of engulfment in the Drosophila ovary: recognition, vesicle uptake, phagosome maturation, and acidification...
2016: Methods in Molecular Biology
Keiko Sakamoto, Yuji Fukushima, Koyu Ito, Michiyuki Matsuda, Shigekazu Nagata, Nagahiro Minato, Masakazu Hattori
Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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