Journal articles on the topic 'Necrotic cell clearance'
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Poon, I. K. H., M. D. Hulett, and C. R. Parish. "Molecular mechanisms of late apoptotic/necrotic cell clearance." Cell Death & Differentiation 17, no. 3 (December 18, 2009): 381–97. http://dx.doi.org/10.1038/cdd.2009.195.
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Poon, Ivan K. H., Mark D. Hulett, and Christopher R. Parish. "Histidine-rich glycoprotein is a novel plasma pattern recognition molecule that recruits IgG to facilitate necrotic cell clearance via FcγRI on phagocytes." Blood 115, no. 12 (March 25, 2010): 2473–82. http://dx.doi.org/10.1182/blood-2009-07-234013.
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Abstract Under normal physiologic conditions, necrotic cells resulting from tissue injury are rapidly removed from the circulation and tissues by phagocytes, thus preventing the exposure of intracellular antigenic and immunostimulatory molecules that can aid the development of autoimmune disease. Histidine-rich glycoprotein (HRG), a relatively abundant plasma glycoprotein, has a multidomain structure that can interact with many ligands including components of the fibrinolytic and immune systems. Recently, it has been reported that HRG can bind strongly to cytoplasmic ligand(s) exposed in necrotic cells to enhance clearance by phagocytes. Here we describe the molecular mechanisms underpinning this process. A complex consisting of both HRG and immunoglobulin G (IgG) was found as necessary to aid necrotic cell uptake by monocytes, predominantly via an FcγRI-dependent mechanism. The findings in this study also show that HRG can potentially interact with anionic phospholipids exposed in necrotic cells. Furthermore, the enhanced phagocytosis of necrotic cells induced by HRG-IgG complexes triggers phagocytes to release proinflammatory cytokines such as interleukin-8 and tumor necrosis factor. Thus, HRG has the unique property of complexing with IgG and facilitating a proinflammatory innate immune response to promote the clearance of necrotic cells.
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Atkin-Smith, Georgia K. "Phagocytic clearance of apoptotic, necrotic, necroptotic and pyroptotic cells." Biochemical Society Transactions 49, no. 2 (April 12, 2021): 793–804. http://dx.doi.org/10.1042/bst20200696.
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Although millions of cells in the human body will undergo programmed cell death each day, dying cells are rarely detected under homeostatic settings in vivo. The swift removal of dying cells is due to the rapid recruitment of phagocytes to the site of cell death which then recognise and engulf the dying cell. Apoptotic cell clearance — the engulfment of apoptotic cells by phagocytes — is a well-defined process governed by a series of molecular factors including ‘find-me’, ‘eat-me’, ‘don't eat-me’ and ‘good-bye’ signals. However, in recent years with the rapid expansion of the cell death field, the removal of other necrotic-like cell types has drawn much attention. Depending on the type of death, dying cells employ different mechanisms to facilitate engulfment and elicit varying functional impacts on the phagocyte, from wound healing responses to inflammatory cytokine secretion. Nevertheless, despite the mechanism of death, the clearance of dying cells is a fundamental process required to prevent the uncontrolled release of pro-inflammatory mediators and inflammatory disease. This mini-review summarises the current understandings of: (i) apoptotic, necrotic, necroptotic and pyroptotic cell clearance; (ii) the functional consequences of dying cell engulfment and; (iii) the outstanding questions in the field.
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Brouckaert, Greet, Michael Kalai, Dmitri V. Krysko, Xavier Saelens, Dominique Vercammen, `Matladi Ndlovu, Guy Haegeman, Katharina D'Herde, and Peter Vandenabeele. "Phagocytosis of Necrotic Cells by Macrophages Is Phosphatidylserine Dependent and Does Not Induce Inflammatory Cytokine Production." Molecular Biology of the Cell 15, no. 3 (March 2004): 1089–100. http://dx.doi.org/10.1091/mbc.e03-09-0668.
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Apoptotic cells are cleared by phagocytosis during development, homeostasis, and pathology. However, it is still unclear how necrotic cells are removed. We compared the phagocytic uptake by macrophages of variants of L929sA murine fibrosarcoma cells induced to die by tumor necrosis factor-induced necrosis or by Fas-mediated apoptosis. We show that apoptotic and necrotic cells are recognized and phagocytosed by macrophages, whereas living cells are not. In both cases, phagocytosis occurred through a phosphatidylserine-dependent mechanism, suggesting that externalization of phosphatidylserine is a general trigger for clearance by macrophages. However, uptake of apoptotic cells was more efficient both quantitatively and kinetically than phagocytosis of necrotic cells. Electron microscopy showed clear morphological differences in the mechanisms used by macrophages to engulf necrotic and apoptotic cells. Apoptotic cells were taken up as condensed membrane-bound particles of various sizes rather than as whole cells, whereas necrotic cells were internalized only as small cellular particles after loss of membrane integrity. Uptake of neither apoptotic nor necrotic L929 cells by macrophages modulated the expression of proinflammatory cytokines by the phagocytes.
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Cao, Longxing, Haishuang Chang, Xiangyi Shi, Chao Peng, and Yongning He. "Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205." Proceedings of the National Academy of Sciences 113, no. 47 (November 7, 2016): 13438–43. http://dx.doi.org/10.1073/pnas.1609331113.
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Clearance of dead cells is critical for maintaining homeostasis and prevents autoimmunity and inflammation. When cells undergo apoptosis and necrosis, specific markers are exposed and recognized by the receptors on phagocytes. DEC205 (CD205) is an endocytotic receptor on dendritic cells with antigen presentation function and has been widely used in immune therapies for vaccine generation. It has been shown that human DEC205 recognizes apoptotic and necrotic cells in a pH-dependent fashion. However, the natural ligand(s) of DEC205 remains unknown. Here we find that keratins are the cellular ligands of human DEC205. DEC205 binds to keratins specifically at acidic, but not basic, pH through its N-terminal domains. Keratins form intermediate filaments and are important for maintaining the strength of cells and tissues. Our results suggest that keratins also function as cell markers of apoptotic and necrotic cells and mediate a pH-dependent pathway for the immune recognition of dead cells.
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Mattos, Matheus, Sofie Vandendriessche, Sara Schuermans, Romy Mittenzwei, Ari Waisman, and Pedro Elias Marques. "Natural antibodies are required for necrotic cell debris clearance and liver repair during necrotic liver injury." Journal of Hepatology 77 (July 2022): S396—S397. http://dx.doi.org/10.1016/s0168-8278(22)01141-2.
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Hirt, U. A., and M. Leist. "Rapid, noninflammatory and PS-dependent phagocytic clearance of necrotic cells." Cell Death & Differentiation 10, no. 10 (September 19, 2003): 1156–64. http://dx.doi.org/10.1038/sj.cdd.4401286.
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Krysko, Dmitri V., Katharina D’Herde, and Peter Vandenabeele. "Clearance of apoptotic and necrotic cells and its immunological consequences." Apoptosis 11, no. 10 (August 24, 2006): 1709–26. http://dx.doi.org/10.1007/s10495-006-9527-8.
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Zhang, Ting, and Siddharth Balachandran. "Bayonets over bombs: RIPK3 and MLKL restrict Listeria without triggering necroptosis." Journal of Cell Biology 218, no. 6 (May 16, 2019): 1773–75. http://dx.doi.org/10.1083/jcb.201905047.
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RIPK3 induces necroptosis by phosphorylating MLKL, which then induces plasma membrane rupture and necrotic cell death. In this issue, Sai et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201810014) show that RIPK3-MLKL signaling in epithelial cells promotes Listeria clearance by directly suppressing cytosolic bacterial replication, without activating cell death.
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Hyde, Dallas M., Lisa A. Miller, Ruth J. McDonald, Mary Y. Stovall, Viviana Wong, Kent E. Pinkerton, Craig D. Wegner, Robert Rothlein, and Charles G. Plopper. "Neutrophils enhance clearance of necrotic epithelial cells in ozone-induced lung injury in rhesus monkeys." American Journal of Physiology-Lung Cellular and Molecular Physiology 277, no. 6 (December 1, 1999): L1190—L1198. http://dx.doi.org/10.1152/ajplung.1999.277.6.l1190.
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To test the hypothesis that neutrophil influx is important for the removal of necrotic airway epithelial cells, rhesus monkeys were treated with a function-blocking monoclonal antibody (MAb) against CD18 followed by exposure to ozone or filtered air. CD18 MAb-treated, ozone-exposed monkeys showed a significant inhibition of neutrophil emigration and an accumulation of necrotic airway epithelial cells. In a subsequent experiment, monkeys were given CD18 MAb or an isotype control immunoglobulin before ozone or filtered-air exposure. Complement 5a was instilled into lobes of the right lung at the end of the exposure. Lavage neutrophils were significantly elevated in the right lobes compared with those in the contralateral left lobes; consequently, there were significantly fewer necrotic cells in the airways of the right lung, whereas large aggregations of necrotic cells were observed in the contralateral airways of the left lung. These data indicate that neutrophil influx in ozone-induced injury in primates is CD18 dependent and that neutrophils contribute to the repair of airway epithelium by removal of injured epithelial cells.
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Cocco, Regina E., and David S. Ucker. "Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure." Molecular Biology of the Cell 12, no. 4 (April 2001): 919–30. http://dx.doi.org/10.1091/mbc.12.4.919.
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The distinction between physiological (apoptotic) and pathological (necrotic) cell deaths reflects mechanistic differences in cellular disintegration and is of functional significance with respect to the outcomes that are triggered by the cell corpses. Mechanistically, apoptotic cells die via an active and ordered pathway; necrotic deaths, conversely, are chaotic and passive. Macrophages and other phagocytic cells recognize and engulf these dead cells. This clearance is believed to reveal an innate immunity, associated with inflammation in cases of pathological but not physiological cell deaths. Using objective and quantitative measures to assess these processes, we find that macrophages bind and engulf native apoptotic and necrotic cells to similar extents and with similar kinetics. However, recognition of these two classes of dying cells occurs via distinct and noncompeting mechanisms. Phosphatidylserine, which is externalized on both apoptotic and necrotic cells, is not a specific ligand for the recognition of either one. The distinct modes of recognition for these different corpses are linked to opposing responses from engulfing macrophages. Necrotic cells, when recognized, enhance proinflammatory responses of activated macrophages, although they are not sufficient to trigger macrophage activation. In marked contrast, apoptotic cells profoundly inhibit phlogistic macrophage responses; this represents a cell-associated, dominant-acting anti-inflammatory signaling activity acquired posttranslationally during the process of physiological cell death.
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Gaipl, Udo S., Thomas D. Beyer, Petra Heyder, Susanne Kuenkele, Andrea Böttcher, Reinhard E. Voll, Joachim R. Kalden, and Martin Herrmann. "Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin." Arthritis & Rheumatism 50, no. 2 (February 2004): 640–49. http://dx.doi.org/10.1002/art.20034.
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Jiang, Ning, Charles F. Reich, and David S. Pisetsky. "Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells." Blood 102, no. 6 (September 15, 2003): 2243–50. http://dx.doi.org/10.1182/blood-2002-10-3312.
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Abstract After apoptosis or necrosis, macrophages clear dead cells by phagocytosis. Although this process is efficient, circulating nucleosomes can occur in certain diseases, presumably reflecting either increased production or impaired clearance. To investigate the generation of blood nucleosomes, graded numbers of apoptotic and necrotic cells were administered to healthy mice, and levels of blood nucleosomes and DNA were determined. Using Jurkat cells as a model, nucleosomes and DNA were detected in the blood after the administration of 108 apoptotic or necrotic cells per mouse by the intraperitoneal route. The kinetics of the response were similar for both types of cells. The role of macrophages was assessed by eliminating these cells with clodronate liposomes or silica. Although clodronate treatment alone produced a peak level of blood DNA, the subsequent administration of dead cells caused no change in DNA levels. In contrast, silica treatment alone did not elicit a blood DNA response, though this treatment limited the rise in DNA from administered cells. Molecular studies showed that the blood DNA following the administration of apoptotic or necrotic cells arose from the mouse and the Jurkat cells, and its size distribution was consistent with apoptosis. Together, these findings suggest that the generation of blood nucleosomes depends on macrophages, with apoptosis a concomitant of a high burden of dead and dying cells.
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Lieberthal, W., and J. S. Levine. "Mechanisms of apoptosis and its potential role in renal tubular epithelial cell injury." American Journal of Physiology-Renal Physiology 271, no. 3 (September 1, 1996): F477—F488. http://dx.doi.org/10.1152/ajprenal.1996.271.3.f477.
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Cells can die by two distinct pathways: apoptosis or necrosis. Necrosis is associated with rapid metabolic collapse that leads to cell swelling, early loss of plasma membrane integrity, and ultimate cell rupture. Cytosolic contents leak from the necrotic cell causing injury and inflammation to surrounding tissue. In contrast, apoptosis is an energy-requiring, gene-directed process, which, when activated, results in cell "suicide." The morphological and biochemical characteristics of cells dying by apoptosis differ markedly from those of cells dying by necrosis. During apoptosis, cells decrease in size and round up. The nuclear chromatin undergoes condensation and fragmentation. The apoptotic cell then breaks apart into many plasma membrane-bound vesicles called "apoptotic bodies," which contain fragments of condensed chromatin and morphologically intact organelles such as mitochondria. Apoptotic cells and bodies are rapidly phagocytosed, thereby protecting surrounding tissues from injury. The rapid and efficient clearance of apoptotic cells makes apoptosis extremely difficult to detect in tissue sections. Recent studies show that multiple cytotoxic stimuli well known to cause necrosis can lead to apoptosis instead when cells are exposed to the same noxious agents at lower concentrations. This insight has led to an interest in the role of apoptosis in the pathogenesis of renal diseases that result primarily from injury to renal tubular epithelial cells. These diseases include acute and chronic renal failure from exposure of the kidney to ischemia or to cytotoxic agents. In this review we discuss some relevant aspects of the differences between necrotic and apoptotic cell death. We also present evidence to support the hypothesis that apoptosis is an important pathogenic mechanism in those forms of acute and chronic renal failure in which the renal tubular epithelial cell is the primary target of ischemic or toxic injury.
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Rovere, Patrizia, Giuseppe Peri, Fausto Fazzini, Barbara Bottazzi, Andrea Doni, Attilio Bondanza, Valérie S. Zimmermann, et al. "The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells." Blood 96, no. 13 (December 15, 2000): 4300–4306. http://dx.doi.org/10.1182/blood.v96.13.4300.
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Abstract Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.
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Rovere, Patrizia, Giuseppe Peri, Fausto Fazzini, Barbara Bottazzi, Andrea Doni, Attilio Bondanza, Valérie S. Zimmermann, et al. "The long pentraxin PTX3 binds to apoptotic cells and regulates their clearance by antigen-presenting dendritic cells." Blood 96, no. 13 (December 15, 2000): 4300–4306. http://dx.doi.org/10.1182/blood.v96.13.4300.h8004300_4300_4306.
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Pentraxins are acute-phase proteins produced in vivo during inflammatory reactions. Classical short pentraxins, C-reactive protein, and serum amyloid P component are generated in the liver in response to interleukin (IL)–6. The long pentraxin PTX3 is produced in tissues under the control of primary proinflammatory signals, such as lipopolysaccharide, IL-1β, and tumor necrosis factor-α, which also promote maturation of dendritic cells (DCs). Cell death commonly occurs during inflammatory reactions. In this study, it is shown that PTX3 specifically binds to dying cells. The binding was dose dependent and saturable. Recognition was restricted to extranuclear membrane domains and to a chronological window after UV irradiation or after CD95 cross-linking–induced or spontaneous cell death in vitro. PTX3 bound to necrotic cells to a lesser extent. Human DCs failed to internalize dying cells in the presence of PTX3, while they took up normally soluble or inert particulate substrates. These results suggest that PTX3 sequesters cell remnants from antigen-presenting cells, possibly contributing to preventing the onset of autoimmune reactions in inflamed tissues.
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Lee, Ji Yun, Shabitha Arumugarajah, Dameng Lian, Natsumi Maehara, Aaron R. Haig, Rita S. Suri, Toru Miyazaki, and Lakshman Gunaratnam. "Recombinant apoptosis inhibitor of macrophage protein reduces delayed graft function in a murine model of kidney transplantation." PLOS ONE 16, no. 4 (April 23, 2021): e0249838. http://dx.doi.org/10.1371/journal.pone.0249838.
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Reperfusion injury following cold and warm ischemia (IRI) is unavoidable during kidney transplantation and contributes to delayed graft function (DGF) and premature graft loss. Death of tubular epithelial cells (TECs) by necrosis during IRI releases pro-inflammatory mediators (e.g. HMGB1), propagating further inflammation (necroinflammation) and tissue damage. Kidney Injury Molecule-1 (KIM-1) is a phagocytic receptor upregulated on proximal TECs during acute kidney injury. We have previously shown that renal KIM-1 protects the graft against transplant associated IRI by enabling TECs to clear apoptotic and necrotic cells, and that recognition of necrotic cells by KIM-1 is augmented in the presence of the opsonin, apoptosis inhibitor of macrophages (AIM). Here, we tested whether recombinant AIM (rAIM) could be used to mitigate transplant associated IRI. We administered rAIM or vehicle control to nephrectomised B6 mice transplanted with a single B6 donor kidney. Compared to grafts in vehicle-treated recipients, grafts from rAIM-treated mice exhibited significantly less renal dysfunction, tubular cell death, tissue damage, tubular obstruction, as well as local and systemic inflammation. Both mouse and human rAIM enhanced the clearance of necrotic cells by murine and human TECs, respectively in vitro. These data support testing of rAIM as a potential therapeutic agent to reduce DGF following kidney transplantation.
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Villeneuve, Julien, Alexis Desmoulière, Antoine Dewitte, Nelly Bordeau, Pierre Costet, Laia Bassaganyas, Jean-Christophe Fricain, Jean Ripoche, and Sébastien Lepreux. "A Role for CD154, the CD40 Ligand, in Granulomatous Inflammation." Mediators of Inflammation 2017 (2017): 1–14. http://dx.doi.org/10.1155/2017/2982879.
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Granulomatous inflammation is a distinctive form of chronic inflammation in which predominant cells include macrophages, epithelioid cells, and multinucleated giant cells. Mechanisms regulating granulomatous inflammation remain ill-understood. CD154, the ligand of CD40, is a key mediator of inflammation. CD154 confers a proinflammatory phenotype to macrophages and controls several macrophagic functions. Here, we studied the contribution of CD154 in a mouse model of toxic liver injury with carbon tetrachloride and a model of absorbable suture graft. In both models, granulomas are triggered in response to endogenous persistent liver calcified necrotic lesions or by grafted sutures. CD154-deficient mice showed delayed clearance of carbon tetrachloride-induced liver calcified necrotic lesions and impaired progression of suture-induced granuloma. In vitro, CD154 stimulated phagocytosis of opsonized erythrocytes by macrophages, suggesting a potential mechanism for the altered granulomatous inflammation in CD154KO mice. These results suggest that CD154 may contribute to the natural history of granulomatous inflammation.
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Elward, Kristina, Mark Griffiths, Masashi Mizuno, Claire L. Harris, Jim W. Neal, B. Paul Morgan, and Philippe Gasque. "CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells." Journal of Biological Chemistry 280, no. 43 (August 8, 2005): 36342–54. http://dx.doi.org/10.1074/jbc.m506579200.
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Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonself-pathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNase-treated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H2O2-treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.
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D’Souza, Shilpa, Seung-Yoon Park, and In-San Kim. "Stabilin-2 acts as an engulfment receptor for the phosphatidylserine-dependent clearance of primary necrotic cells." Biochemical and Biophysical Research Communications 432, no. 3 (March 2013): 412–17. http://dx.doi.org/10.1016/j.bbrc.2013.01.133.
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Kholmukhamedov, Andaleb, and Shawn M. Jobe. "Necrotic but Not Apoptotic Platelets Are Functionally Procoagulant." Blood 132, Supplement 1 (November 29, 2018): 2420. http://dx.doi.org/10.1182/blood-2018-99-116972.
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Abstract There are numerous modes of cell death in mammalian cells. In platelets the primary identified modes are apoptosis and necrosis. Apoptosis is a form of programmed cell death, and in platelets it is considered to be important in their clearance. Besides pyknosis (cell shrinkage) and engulfment by resident phagocytes in vivo, a characteristic feature of apoptosis in nucleated cells is retraction of pseudopodia. However, in platelets, this does not occur. Instead, distinct from that which occurs during activation, lamelopodia and filopodia are not observed in apoptotic platelets suggesting that they have a limited potential to actively participate in coagulation. Necrosis, either regulated or pathologic, is characterized by cytoplasmic swelling (oncosis), swelling of cytoplasmic organelles, and, in later stages, rupture of the plasma membrane. Additionally, secondary necrosis can occur as a consequence of the activation of apoptotic pathways. Apoptosis is an ATP requiring process. In instances when an apoptotic signal was initiated and insufficient ATP is present for the completion of apoptosis, this ATP-depleted cell will undergo death with morphologic features of necrosis. Procoagulant platelets are those platelets that are capable of supporting the assembly of functional tenase and prothrombinase complexes. Due to the increased complexity of experiments demonstrating functional activity, the ability to support procoagulant activity has been presumed in subpopulations of platelets with variable degrees of phosphatidylserine exposure. Here we investigated the procoagulant function and the extent of PSer exposure in platelets undergoing different modes of cell death. Washed human platelets were stimulated with the BH-3 mimetic ABT-737 (100 nM) (apoptotic initiator) or convulxin (250 ng/mL, CVX) (initiator of regulated necrosis). The extent of PSer externalization was estimated by cytometric evaluation of annexin V (AnnV) binding, and functional activity was assessed using tissue factor-initiated thrombinoscopy. Upon stimulation two distinct subpopulations of PSer exposing platelets with "low" and "high" AnnV binding could be distinguished. In CVX-stimulated platelets only a single subpopulation ("high") of PSer exposing platelets could be distinguished. But in platelets stimulated with the apoptotic initiator ABT-737 both "low" and "high" subpopulations of AnnV binding platelets could readily be discerned. To assess the procoagulant functionality of these various modes of cell death ABT-737 (generating ~38% "high" and ~46% "low" AnnV positive platelets) and CVX (~33% "high" AnnV) stimulated platelets were compared by thrombinoscopy. Relative to unstimulated platelets, inclusion of CVX-stimulated platelets within the reaction significantly shortened both the lag time (~5 to ~3 min (p<0.05)) and time to peak thrombin (~13 to ~8 min (p<0.05)). These shortened response times were accompanied by a ~2-fold increase in peak thrombin (p<0.05). In contrast to the potentiating effects of CVX-stimulation, ABT-737 stimulation had no effect on measures of thrombin; this despite having equivalent (when assessing only high) or even a greater percentage of AnnV binding (when assessing low and high). These results are the first to differentiate the mode of platelet cell death and its corresponding effects on PSer exposure and a functional measure of procoagulant function. Apoptotic and necrotic platelets are not only distinguished by their molecular mechanism of initiation, but also by their functional ability to support coagulation. Only platelets undergoing cell death by necrotic pattern were functionally procoagulant as measured by direct prothrombinase activity. Advancement in understanding the principles of cell death in procoagulant platelet formation might be beneficial for the determination and guidance of novel pharmacological strategy targeted for the treatment of procoagulant related hematopathologies. Disclosures Jobe: CSL: Consultancy; Shire: Consultancy; Octapharma: Consultancy.
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Kemper, Claudia, Lynne M. Mitchell, and Dennis E. Hourcade. "Properdin: Cell Death’s Little Helper? (53.3)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S104. http://dx.doi.org/10.4049/jimmunol.178.supp.53.3.
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Abstract Apoptosis is a mechanism for the safe elimination of undesirable cells without evoking an immune response. C3b/C4b-opsonization of apoptotic cells through classical and lectin complement pathway activation is a major mechanism to mark these cells for clearance by scavenger cells. Recently we observed that the serum protein properdin bound to a biosensor surface leads to direct alternative pathway activation. Here we determine whether properdin can also direct complement activation to physiological targets i.e. human apoptotic T cells. We found that: Properdin (purified and in serum) binds apoptotic and necrotic CD4+ T cells, but neither non-activated nor viable activated T cells;Properdin bound to apoptotic cells initiates de novo complement activation and phagocytosis by dendritic cells/macrophages;Surprisingly, properdin also enhanced phagocytosis of apoptotic cells independently of complement activation. We propose that properdin directly recognizes apoptotic T cells, promoting their targeted uptake by phagocytes. This mechanism represents a novel pathway for the identification and removal of undesired cells. Funded by NIH R01 AI05143 (to DH).
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P., Manasa, Dhanapala N., Pruthvi Raj S., Architha Menon P., Rahul Gopi, Theerta V. M., and Shwetha Kumari C. "Orbital involvement in COVID-19 associated mucormycosis." International Journal of Research in Medical Sciences 11, no. 2 (January 25, 2023): 673–77. http://dx.doi.org/10.18203/2320-6012.ijrms20230183.
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Background: Mucormycosis is an opportunistic, potentially lethal, fungal infection predisposed by uncontrolled diabetes mellitus, immunosuppressive therapy, primary or secondary immunodeficiency, injudicious use of corticosteroids, hematological malignancies, hematological stem cell transplantation, solid organ malignancies, solid organ transplantation. Rhino-orbital mucormycosis is the commonest form of mucormycosis. This study was done to discuss the management strategies (orbital decompression/clearance, orbital exenteration, retrobulbar amphotericin B) in the treatment of orbital mucormycosis and its clinical outcomes. Methods: A retrospective descriptive study was conducted between May 2021 and October 2021 at Bowring and Lady Curzon hospital, Shri Atal Bihari Vajpayee Medical College and Research Institute, Karnataka, India. 181 patients with post-COVID RTPCR negative rhino-orbital mucormycosis were included in the study. Patients underwent endoscopic orbital clearance, orbital exenteration based on the extent of orbital involvement. Results: 143 were males and 38 were females. 160 patients underwent orbital decompression and clearance of necrotic tissue. 21 patients underwent orbital exenteration. Final visual acuity of perception of light (PL) positive and above was achieved in 147 patients. 57/58 (98.27%) patients had improvement in extraocular movements post-surgery and resolution of diplopia after orbital decompression/clearance. Conclusions: Endoscopic orbital clearance helps to reduce the need for orbital exenteration in PL negative patients. TRAmB as adjuvant helps in decreasing the ocular morbidity. Orbital exenteration is best avoided, when possible, to avoid cosmetic disfigurement and psychological trauma to the patient.
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Zapuskalov, I. V., O. I. Krivosheina, and N. A. Levchenko. "Inflammatory regenerative processes dynamics with corneal ulcer against the background of usage of blood autologous mononuclear leukocyte." Bulletin of Siberian Medicine 10, no. 1 (February 28, 2011): 38–42. http://dx.doi.org/10.20538/1682-0363-2011-1-38-42.
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In the experiment in vivo the mechanisms of the development of inflammatory regenerative processes with corneal ulcer against the background of the instillations of blood autologous mononuclear leukocyte and traditional pharmacotherapy are studied. It is determined that against the background of the use of blood autologous mononuclear leukocyte the duration and the intensity of inflammation reduce and the clearance of ulcer defect from necrotic mass accelerates. The instillations of blood autologous mononuclear leukocyte against the background of traditional pharmacotherapy of experimental corneal ulcer stimulate fast change of cell phases in the inflammation center and activate the process of regeneration of damaged cornea structures.
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Balança, Baptiste, Laurent Desmurs, Jérémy Grelier, Armand Perret-Liaudet, and Anne-Claire Lukaszewicz. "DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2439. http://dx.doi.org/10.3390/ijms22052439.
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Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives
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Chen, Liang, Zhongyi Zhou, Cheng Hu, Manfred F. Maitz, Li Yang, Rifang Luo, and Yunbing Wang. "Platelet Membrane-Coated Nanocarriers Targeting Plaques to Deliver Anti-CD47 Antibody for Atherosclerotic Therapy." Research 2022 (January 17, 2022): 1–12. http://dx.doi.org/10.34133/2022/9845459.
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Atherosclerosis, the principle cause of cardiovascular disease (CVD) worldwide, is mainly characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Atherogenesis is associated with the upregulation of CD47, a key antiphagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or “efferocytosis.” Here, we have developed platelet membrane-coated mesoporous silicon nanoparticles (PMSN) as a drug delivery system to target atherosclerotic plaques with the delivery of an anti-CD47 antibody. Briefly, the cell membrane coat prolonged the circulation of the particles by evading the immune recognition and provided an affinity to plaques and atherosclerotic sites. The anti-CD47 antibody then normalized the clearance of diseased vascular tissue and further ameliorated atherosclerosis by blocking CD47. In an atherosclerosis model established in ApoE−/− mice, PMSN encapsulating anti-CD47 antibody delivery significantly promoted the efferocytosis of necrotic cells in plaques. Clearing the necrotic cells greatly reduced the atherosclerotic plaque area and stabilized the plaques reducing the risk of plaque rupture and advanced thrombosis. Overall, this study demonstrated the therapeutic advantages of PMSN encapsulating anti-CD47 antibodies for atherosclerosis therapy, which holds considerable promise as a new targeted drug delivery platform for efficient therapy of atherosclerosis.
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Bretz, Camille, Geoff Gersuk, Sue Knoblaugh, Neelkamal Chaudhary, Julie Randolph-Habecker, Robert C. Hackman, Janet Staab, and Kieren A. Marr. "MyD88 Signaling Contributes to Early Pulmonary Responses to Aspergillus fumigatus." Infection and Immunity 76, no. 3 (November 26, 2007): 952–58. http://dx.doi.org/10.1128/iai.00927-07.
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ABSTRACT Toll-like receptors and the β-glucan receptor, dectin-1, mediate macrophage inflammatory responses to Aspergillus fumigatus through MyD88-dependent and -independent signaling mechanisms; however, pulmonary inflammatory responses in MyD88-deficient mice challenged with A. fumigatus are poorly defined. The role of MyD88 signaling in early pulmonary inflammation and fungal clearance was evaluated in C57BL/6J wild-type (WT) and MyD88-deficient (MyD88−/−) mice. Early (<48 h) after infection, MyD88−/− mice had higher fungal burdens than those of WT mice, although fungal burdens rapidly declined (>72 h) in both. MyD88−/− mice had less consolidated inflammation, with fewer NK cells, in lung tissue early (24 h) after infection than did WT mice. At the latter time point, MyD88−/− mouse lungs were characterized by a large amount of necrotic cellular debris and fibrin, while WT lungs had organized inflammation. Although there were equivalent numbers of macrophages in WT and MyD88−/− mouse lung tissues, MyD88−/− cells demonstrated delayed uptake of green fluorescent protein-expressing A. fumigatus (GFP-Af293); histologically, MyD88−/− mouse lungs had more hyphal invasion of terminal airways and vessels, the appearance of bronchiolar epithelial cell necrosis, and necrotizing vasculitis. MyD88−/− lung homogenates contained comparatively decreased amounts of interleukin-1β (IL-1β), IL-6, KC, and gamma interferon and paradoxically increased amounts of tumor necrosis factor alpha and macrophage inflammatory protein 1α. These data indicate that the MyD88-dependent pathway mediates acute pulmonary fungal clearance, inflammation, and tissue injury very early after infection. Resolution of abnormalities within a 3-day window demonstrates the importance of redundant signaling pathways in mediating pulmonary inflammatory responses to fungi.
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Poon, Ivan K. H., Kruti K. Patel, David S. Davis, Christopher R. Parish, and Mark D. Hulett. "Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma." Blood 117, no. 7 (February 17, 2011): 2093–101. http://dx.doi.org/10.1182/blood-2010-09-303842.
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AbstractHistidine-rich glycoprotein (HRG), also known as histidine-proline-rich glyco-protein, is an abundant and well-characterized protein of vertebrate plasma. HRG has a multidomain structure that allows the molecule to interact with many ligands, including heparin, phospholipids, plasminogen, fibrinogen, immunoglobulin G, C1q, heme, and Zn2+. The ability of HRG to interact with various ligands simultaneously has suggested that HRG can function as an adaptor molecule and regulate numerous important biologic processes, such as immune complex/necrotic cell/pathogen clearance, cell adhesion, angiogenesis, coagulation, and fibrinolysis. The present review covers the proposed multifunctional roles of HRG with a focus on recent findings that have led to its emergence as a key regulator of immunity and vascular biology. Also included is a discussion of the striking functional similarities between HRG and other important multifunctional proteins found in plasma, such as C-reactive protein, C1q, β2 glycoprotein I, and thrombospondin-1.
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Jo, Gayoung, Eun Jeong Kim, Min Ho Park, and Hoon Hyun. "Tumor Targeting with Methotrexate-Conjugated Zwitterionic Near-Infrared Fluorophore for Precise Photothermal Therapy." International Journal of Molecular Sciences 23, no. 22 (November 16, 2022): 14127. http://dx.doi.org/10.3390/ijms232214127.
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Targeted tumor imaging can effectively enable image-guided surgery and precise cancer therapy. Finding the right combination of anticancer drugs and near-infrared (NIR) fluorophores is the key to targeted photothermal cancer treatment. In this study, a tumor-targetable NIR fluorophore conjugate with rapid body clearance was developed for accurate tumor imaging and effective photothermal therapy (PTT). The methotrexate (MTX) and zwitterionic NIR fluorophore conjugate (MTX-ZW) were prepared by conjugating a folate antagonist MTX with an aminated ZW800-1 analog to increase the tumor targetability for NIR laser-based PTT of cancer. The MTX, known as a poor tumor-selective drug, showed high tumor accumulation and rapid background clearance after conjugation with the highly water-soluble zwitterionic NIR fluorophore up to 4 h post-injection. The photothermal energy was generated from the MTX-ZW conjugate to induce necrotic cell death in the targeted tumor site under 808 nm laser irradiation. Compared with the previously reported MTX conjugates, the MTX-ZW conjugate can be a great candidate for targeted tumor imaging and fluorescence-guided photothermal cancer therapy. Therefore, these results provide a strategy for the design of drug-fluorophore conjugates and elaborate therapeutic platforms for cancer phototherapy.
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Wood, Gwendolyn E., Susan M. Dutro, and Patricia A. Totten. "Haemophilus ducreyi Inhibits Phagocytosis by U-937 Cells, a Human Macrophage-Like Cell Line." Infection and Immunity 69, no. 8 (August 1, 2001): 4726–33. http://dx.doi.org/10.1128/iai.69.8.4726-4733.2001.
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ABSTRACT Haemophilus ducreyi is a gram-negative obligate human pathogen that causes the genital ulcer disease chancroid. Chancroid lesions are deep necrotic ulcers with an immune cell infiltrate that includes macrophages. Despite the presence of these phagocytic cells, chancroid ulcers can persist for months and live H. ducreyi can be isolated from these lesions. To analyze the interaction of H. ducreyi with macrophages, we investigated the ability of H. ducreyi strain 35000 to adhere to, invade, and survive within U-937 cells, a human macrophage-like cell line. We found that although H. ducreyi strain 35000 adhered efficiently to U-937 cells, few bacteria were internalized, suggesting that H. ducreyiavoids phagocytosis by human macrophages. The few bacteria that were phagocytosed in these experiments were rapidly killed. We also found that H. ducreyi inhibits the phagocytosis of a secondary target (opsonized sheep red blood cells). Antiphagocytic activity was found in logarithmic, stationary-phase, and plate-grown cultures and was associated with whole, live bacteria but not with heat-killed cultures, sonicates, or culture supernatants. Phagocytosis was significantly inhibited after a 15-min exposure to H. ducreyi, and a multiplicity of infection of approximately 1 CFU per macrophage was sufficient to cause a significant reduction in phagocytosis by U-937 cells. Finally, all of nine H. ducreyi strains tested were antiphagocytic, suggesting that this is a common virulence mechanism for this organism. This finding suggests a mechanism by which H. ducreyi avoids killing and clearance by macrophages in chancroid lesions and inguinal lymph nodes.
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Huang, Kai, Bingyuan Lin, Yiyang Liu, Haiyong Ren, and Qiaofeng Guo. "Correlation Analysis between Chronic Osteomyelitis and Bacterial Biofilm." Stem Cells International 2022 (September 8, 2022): 1–8. http://dx.doi.org/10.1155/2022/9433847.
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Objective. To study the role of bacterial biofilm (BBF) in the formation of chronic osteomyelitis and its prevention and treatment. Methods. In this paper, a large amount of relevant literature was searched for analysis and summary, and the key words “chronic osteomyelitis,” “bacterial biofilm,” “infection,” and “debridement” were searched in databases, mainly CNKI, Wanfang, and Wipu. The search was conducted until December 2020. The role of bacterial biofilm formation in chronic osteomyelitis and its prevention were analyzed. Results. Chronic osteomyelitis is formed mainly due to poor blood supply and drug-resistant bacteria, of which cellular biofilm is the most important cause. BBF forms on the surface of necrotic soft tissue and bone tissue, which has a protective effect on bacteria and greatly enhances their resistance to antibiotics, leading to difficulties in complete bacterial clearance and recurrent infections in osteomyelitis. Conclusion. Through an in-depth study of the molecular biology and signal transduction of osteomyelitis biofilm, antibiotic biofilm treatment strategies and surgical debridement remain the focus of clinical translation of chronic osteomyelitis.
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Radsak, Markus P., Norbert Hilf, Harpreet Singh-Jasuja, Sibylla Braedel, Peter Brossart, Hans-Georg Rammensee, and Hansjoerg Schild. "The heat shock protein Gp96 binds to human neutrophils and monocytes and stimulates effector functions." Blood 101, no. 7 (April 1, 2003): 2810–15. http://dx.doi.org/10.1182/blood-2002-07-2261.
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The endoplasmic reticulum (ER)–resident heat shock protein Gp96 is involved in protein folding and is released into the extracellular space after necrotic cell death. In this context, Gp96 has immunostimulatory properties: it activates dendritic cells or macrophages and delivers associated peptides into the antigen presentation pathway, resulting in the induction of specific T-cell responses. The inflammatory response after necrotic tissue damage leads to the recruitment of polymorphonuclear neutrophils (PMNs) and monocytes, allowing them to make their first encounter with Gp96. We therefore investigated whether PMNs and monocytes interact with Gp96. We were able to show that PMNs and monocytes specifically bind fluorescein isothiocyanate (FITC)–conjugated Gp96. The binding of Gp96-FITC was competed by lipopolysaccharide (LPS) or fucoidan, a known inhibitor of scavenger receptors. Interestingly, the binding of LPS-FITC was also competed not only by fucoidan, but by Gp96, suggesting that LPS and Gp96 share a common receptor on PMNs. One important effector function of PMNs is the clearance of an inflammatory site by phagocytosis. We therefore assessed the influence of Gp96 on phagocytic activity using fluorochrome-labeled polystyrene beads. We found a marked enhancement of phagocytosis in the presence of Gp96 and concluded that PMNs not only bind Gp96, but are also activated by it. Additionally, Gp96-stimulated PMNs and especially monocytes release large amounts of interleukin-8, a potent neutrophil-attracting chemokine. In conclusion, we demonstrate that Gp96 specifically binds to and activates PMNs and monocytes, extending the function of Gp96 as a danger signal to additional members of the innate immune system.
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Linnemann, Lara C., Ulrich E. Schaible, and Tobias K. Dallenga. "Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo." International Journal of Molecular Sciences 23, no. 5 (February 25, 2022): 2554. http://dx.doi.org/10.3390/ijms23052554.
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Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo.
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Song, Haichao, Bintong Yang, Ying Li, Aidong Qian, Yuanhuan Kang, and Xiaofeng Shan. "Focus on the Mechanisms and Functions of Pyroptosis, Inflammasomes, and Inflammatory Caspases in Infectious Diseases." Oxidative Medicine and Cellular Longevity 2022 (January 29, 2022): 1–21. http://dx.doi.org/10.1155/2022/2501279.
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Eukaryotic cells can initiate several distinct self-destruction mechanisms to display essential roles for the homeostasis maintenance, development, and survival of an organism. Pyroptosis, a key response mode in innate immunity, also referred to as caspase-1-dependent proinflammatory programmed necrotic cell death activated by human caspase-1/4/5, or mouse caspase-1/11, plays indispensable roles in response to cytoplasmic insults and immune defense against infectious diseases. These inflammatory caspases are employed by the host to eliminate pathogen infections such as bacteria, viruses, protozoans, and fungi. Gasdermin D requires to be cleaved and activated by these inflammatory caspases to trigger the pyroptosis process. Physiological rupture of cells results in the release of proinflammatory cytokines, the alarmins IL-1β and IL-18, symbolizing the inflammatory potential of pyroptosis. Moreover, long noncoding RNAs play direct or indirect roles in the upstream of the pyroptosis trigger pathway. Here, we review in detail recently acquired insights into the central roles of inflammatory caspases, inflammasomes, and pyroptosis, as well as the crosstalk between pyroptosis and long noncoding RNAs in mediating infection immunity and pathogen clearance.
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Appelt, U., A. Sheriff, U. S. Gaipl, J. R. Kalden, R. E. Voll, and M. Herrmann. "Viable, apoptotic and necrotic monocytes expose phosphatidylserine: cooperative binding of the ligand Annexin V to dying but not viable cells and implications for PS-dependent clearance." Cell Death & Differentiation 12, no. 2 (November 12, 2004): 194–96. http://dx.doi.org/10.1038/sj.cdd.4401527.
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Santos, Leonardo Duarte, Krist Helen Antunes, Stéfanie Primon Muraro, Gabriela Fabiano de Souza, Amanda Gonzalez da Silva, Jaqueline de Souza Felipe, Larissa Cardoso Zanetti, et al. "TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection." European Respiratory Journal 57, no. 6 (December 10, 2020): 2003764. http://dx.doi.org/10.1183/13993003.03764-2020.
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Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3−/− mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue.Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1−/− mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.
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Yamaguchi, Pantarat, Suzuki, and Evdokiou. "Near-Infrared Photoimmunotherapy Using a Small Protein Mimetic for HER2-Overexpressing Breast Cancer." International Journal of Molecular Sciences 20, no. 23 (November 20, 2019): 5835. http://dx.doi.org/10.3390/ijms20235835.
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Near-infrared photoimmunotherapy (NIR-PIT) is a new and promising cancer therapy based on a monoclonal antibody conjugated to a photosensitizer which is activated by near-infrared light irradiation, causing cell death. We investigated NIR-PIT using a small protein mimetic (6–7 kDa), Affibody molecules, instead of a monoclonal antibody for HER2-overexpressing cancer. Because of its small size, the Affibody has rapid clearance, high imaging contrast, and good tumor penetration. Due to the small size of the Affibodies, which can cross the blood–brain barrier, NIR-PIT using Affibodies has the potential to extend the target cancer of NIR-PIT, including brain metastases. In vitro, NIR-PIT using HER2 Affibody–IR700Dye conjugates induced the selective destruction of HER2-overexpressing breast cancer cells without damage to control cells having low level expression of HER2. HER2-overexpressing cancer cells showed necrotic cell death and their viability maintained at low levels, even 5 days after NIR-PIT. In contrast, treatment with high concentration of HER2 Affibody–IR700Dye conjugate alone or irradiation with high dose of NIR light alone was without effect on cell viability. Affibody and IR700Dye are currently used clinically, and therefore, we would expect the current formulation to be safely and quickly transitioned into clinical trials.
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Moyron-Quiroz, Juan, Jeanette Ampudia, and Xifeng Yang. "Trem-like 4-expressing dendritic cells and macrophages exhibit distinct inflammatory chemokine receptors (173.33)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 173.33. http://dx.doi.org/10.4049/jimmunol.188.supp.173.33.
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Abstract Trem-like 4 (Treml4) is a recently identified type I transmembrane protein, member of the Trem (Triggering receptor expressed on myeloid cells) family. It is mainly expressed on splenic CD8α+ dendritic cells (DCs) and marginal metallophilic and red pulp macrophages. The natural ligand of Treml4 remains to be identified, but a fusion protein containing the extracellular domains of Treml4 is able to bind apoptotic and necrotic cells, suggesting it potentially plays a role in the clearance of dead cells, a process associated with anti-inflammatory and immunosuppressive effects. To further characterize the cell subsets expressing Treml4, we stained splenic DCs and macrophages with various flourochrome conjugated antibodies, including the anti-Treml4 antibody, 16E5. Our data demonstrated that both Treml4+ DCs and macrophages also express CCR6, but neither population expresses CXCR2 nor CCR5. In addition, Treml4+ DCs, but not Treml4+ macrophages, express CXCR3. Conversely, Treml4+ macrophages, but not Treml4+ DCs, express the receptor for the anaphylatoxin C5a. Taken together, these findings suggest that Treml4+ DCs and Treml4+ macrophages might be recruited to inflammation sites depending on the different chemoattractants produced.
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Fernandez-Castaneda, Anthony, Sanja Arandjelovic, Travis L. Stiles, Ryan K. Schlobach, Kerri A. Mowen, Steven L. Gonias, and Alban Gaultier. "Identification of the Low Density Lipoprotein (LDL) Receptor-related Protein-1 Interactome in Central Nervous System Myelin Suggests a Role in the Clearance of Necrotic Cell Debris." Journal of Biological Chemistry 288, no. 7 (December 21, 2012): 4538–48. http://dx.doi.org/10.1074/jbc.m112.384693.
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Marée, Athanasius F. M., Richard Kublik, Diane T. Finegood, and Leah Edelstein-Keshet. "Modelling the onset of Type 1 diabetes: can impaired macrophage phagocytosis make the difference between health and disease?" Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 364, no. 1842 (March 22, 2006): 1267–82. http://dx.doi.org/10.1098/rsta.2006.1769.
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A wave of apoptosis (programmed cell death) occurs normally in pancreatic β-cells of newborn mice. We previously showed that macrophages from non-obese diabetic (NOD) mice become activated more slowly and engulf apoptotic cells at a lower rate than macrophages from control (Balb/c) mice. It has been hypothesized that this low clearance could result in secondary necrosis, escalating inflammation and self-antigen presentation that later triggers autoimmune, Type 1 diabetes (T1D). We here investigate whether this hypothesis could offer a reasonable and parsimonious explanation for onset of T1D in NOD mice. We quantify variants of the Copenhagen model (Freiesleben De Blasio et al . 1999 Diabetes 48 , 1677), based on parameters from NOD and Balb/c experimental data. We show that the original Copenhagen model fails to explain observed phenomena within a reasonable range of parameter values, predicting an unrealistic all-or-none disease occurrence for both strains. However, if we take into account that, in general, activated macrophages produce harmful cytokines only when engulfing necrotic (but not apoptotic) cells, then the revised model becomes qualitatively and quantitatively reasonable. Further, we show that known differences between NOD and Balb/c mouse macrophage kinetics are large enough to account for the fact that an apoptotic wave can trigger escalating inflammatory response in NOD, but not Balb/c mice. In Balb/c mice, macrophages clear the apoptotic wave so efficiently, that chronic inflammation is prevented.
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Altevogt, Peter, Marei Sammar, Laura Hüser, Viktor Umansky, and Jochen Utikal. "Perspective – Escape from destruction: how cancer-derived EVs are protected from phagocytosis." Extracellular vesicles as biomarkers – in pathophysiology, physical education and home office? 2, no. 1 (September 2, 2020): 60–64. http://dx.doi.org/10.47184/tev.2020.01.08.
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There is evidence that cancer-derived extracellular vesicles (EVs) have nearby and distant effects in the body. In order to reach distant sites, EVs need to travel through the blood stream and organs where they encounter a hostile environment in the form or phagocytic cells. However, the stability and homeostasis in the blood circulation and in the tumor microenvironment are not well understood. Phagocytosis is an important mechanism for the clearance of apoptotic and necrotic cells. As exosomes (small EV) express “eat-me” signals such as phosphatidyl-serine, it is likely that they are cleared similar to dead cells. Here we discuss measures that cancer cells have developed to protect their EVs from rapid depletion. The expression of “don’t eat me” signals such as CD47 and CD24 on the tumor cell surface and in released exosomes is of vital importance. We will focus on the role of the CD24-Siglec-10 binding axis as a stop signal at the interface between tumor cells and phagocytic cells. Extending the lifetime of EVs is essential for the cancer to achieve systemic immune suppression and to prepare metastatic niches for spreading. Keywords: CD24, CD47, Extracellular vesicles, Siglecs, carbohydrates, phagocytosis
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Giannelou, Angeliki, Hongying Wang, Qing Zhou, Yong Hwan Park, Mones S. Abu-Asab, Kris Ylaya, Deborah L. Stone, et al. "Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors." Annals of the Rheumatic Diseases 77, no. 4 (January 22, 2018): 612–19. http://dx.doi.org/10.1136/annrheumdis-2017-212401.
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ObjectivesTo characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.MethodsWe studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).ResultsWe identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.ConclusionsMutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
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Andleeb, Anisa, Aneeta Andleeb, Salman Asghar, Gouhar Zaman, Muhammad Tariq, Azra Mehmood, Muhammad Nadeem, Christophe Hano, Jose M. Lorenzo, and Bilal Haider Abbasi. "A Systematic Review of Biosynthesized Metallic Nanoparticles as a Promising Anti-Cancer-Strategy." Cancers 13, no. 11 (June 5, 2021): 2818. http://dx.doi.org/10.3390/cancers13112818.
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Cancer is one of the foremost causes of death worldwide. Cancer develops because of mutation in genes that regulate normal cell cycle and cell division, thereby resulting in uncontrolled division and proliferation of cells. Various drugs have been used to treat cancer thus far; however, conventional chemotherapeutic drugs have lower bioavailability, rapid renal clearance, unequal delivery, and severe side effects. In the recent years, nanotechnology has flourished rapidly and has a multitude of applications in the biomedical field. Bio-mediated nanoparticles (NPs) are cost effective, safe, and biocompatible and have got substantial attention from researchers around the globe. Due to their safe profile and fewer side effects, these nanoscale materials offer a promising cure for cancer. Currently, various metallic NPs have been designed to cure or diagnose cancer; among these, silver (Ag), gold (Au), zinc (Zn) and copper (Cu) are the leading anti-cancer NPs. The anticancer potential of these NPs is attributed to the production of reactive oxygen species (ROS) in cellular compartments that eventually leads to activation of autophagic, apoptotic and necrotic death pathways. In this review, we summarized the recent advancements in the biosynthesis of Ag, Au, Zn and Cu NPs with emphasis on their mechanism of action. Moreover, nanotoxicity, as well as the future prospects and opportunities of nano-therapeutics, are also highlighted.
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Wellmer, Andreas, Matthias von Mering, Annette Spreer, Ricarda Diem, Helmut Eiffert, Christiane Noeske, Stefanie Bunkowski, Ralf Gold, and Roland Nau. "Experimental Pneumococcal Meningitis: Impaired Clearance of Bacteria from the Blood Due to Increased Apoptosis in the Spleen in Bcl-2-Deficient Mice." Infection and Immunity 72, no. 6 (June 2004): 3113–19. http://dx.doi.org/10.1128/iai.72.6.3113-3119.2004.
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ABSTRACT Necrotic and apoptotic neuronal cell death can be found in pneumococcal meningitis. We investigated the role of Bcl-2 as an antiapoptotic gene product in pneumococcal meningitis using Bcl-2 knockout (Bcl-2−/−) mice. By using a model of pneumococcal meningitis induced by intracerebral infection, Bcl-2-deficient mice and control littermates were assessed by clinical score and a tight rope test at 0, 12, 24, 32, and 36 h after infection. Then mice were sacrificed, the bacterial titers in blood, spleen, and cerebellar homogenates were determined, and the brain and spleen were evaluated histologically. The Bcl-2-deficient mice developed more severe clinical illness, and there were significant differences in the clinical score at 24, 32, and 36 h and in the tight rope test at 12 and 32 h. The bacterial titers in the blood were greater in Bcl-2-deficient mice than in the controls (7.46 ± 1.93 log CFU/ml versus 5.16 ± 0.96 log CFU/ml [mean ± standard deviation]; P < 0.01). Neuronal damage was most prominent in the hippocampal formation, but there were no significant differences between groups. In situ tailing revealed only a few apoptotic neurons in the brain. In the spleen, however, there were significantly more apoptotic leukocytes in Bcl-2-deficient mice than in controls (5,148 ± 3,406 leukocytes/mm2 versus 1,070 ± 395 leukocytes/mm2; P < 0.005). Bcl-2 appears to counteract sepsis-induced apoptosis of splenic lymphocytes, thereby enhancing clearance of bacteria from the blood.
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Baggaley, Erin M., Austin C. Elliott, and Jason I. E. Bruce. "Oxidant-induced inhibition of the plasma membrane Ca2+-ATPase in pancreatic acinar cells: role of the mitochondria." American Journal of Physiology-Cell Physiology 295, no. 5 (November 2008): C1247—C1260. http://dx.doi.org/10.1152/ajpcell.00083.2008.
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Impairment of the normal spatiotemporal pattern of intracellular Ca2+ ([Ca2+]i) signaling, and in particular, the transition to an irreversible “Ca2+ overload” response, has been implicated in various pathophysiological states. In some diseases, including pancreatitis, oxidative stress has been suggested to mediate this Ca2+ overload and the associated cell injury. We have previously demonstrated that oxidative stress with hydrogen peroxide (H2O2) evokes a Ca2+ overload response and inhibition of plasma membrane Ca2+-ATPase (PMCA) in rat pancreatic acinar cells (Bruce JI and Elliott AC. Am J Physiol Cell Physiol 293: C938–C950, 2007). The aim of the present study was to further examine this oxidant-impaired inhibition of the PMCA, focusing on the role of the mitochondria. Using a [Ca2+]i clearance assay in which mitochondrial Ca2+ uptake was blocked with Ru-360, H2O2 (50 μM–1 mM) markedly inhibited the PMCA activity. This H2O2-induced inhibition of the PMCA correlated with mitochondrial depolarization (assessed using tetramethylrhodamine methylester fluorescence) but could occur without significant ATP depletion (assessed using Magnesium Green fluorescence). The H2O2-induced PMCA inhibition was sensitive to the mitochondrial permeability transition pore (mPTP) inhibitors, cyclosporin-A and bongkrekic acid. These data suggest that oxidant-induced opening of the mPTP and mitochondrial depolarization may lead to an inhibition of the PMCA that is independent of mitochondrial Ca2+ handling and ATP depletion, and we speculate that this may involve the release of a mitochondrial factor. Such a phenomenon may be responsible for the Ca2+ overload response, and for the transition between apoptotic and necrotic cell death thought to be important in many disease states.
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Falcone, Domenick J., Wolfgang Borth, K. M. Faisal Khan, and Katherine A. Hajjar. "Plasminogen-mediated matrix invasion and degradation by macrophages is dependent on surface expression of annexin II." Blood 97, no. 3 (February 1, 2001): 777–84. http://dx.doi.org/10.1182/blood.v97.3.777.
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Abstract Genetic evidence demonstrates the importance of plasminogen activation in the migration of macrophages to sites of injury and inflammation, their removal of necrotic debris, and their clearance of fibrin. These studies identified the plasminogen binding protein annexin II on the surface of macrophages and determined its role in their ability to degrade and migrate through extracellular matrices. Calcium-dependent binding of annexin II to RAW264.7 macrophages was shown using flow cytometry and Western blot analysis of EGTA eluates. Ligand blots demonstrated that annexin II comigrates with one of several proteins in lysates and membranes derived from RAW264.7 macrophages that bind plasminogen. Preincubation of RAW264.7 macrophages with monoclonal anti–annexin II IgG inhibited (35%) their binding of 125I-Lys-plasminogen. Likewise, plasmin binding to human monocyte-derived macrophages and THP-1 monocytes was inhibited (50% and 35%, respectively) when cells were preincubated with anti–annexin II IgG. Inhibition of plasminogen binding to annexin II on RAW264.7 macrophages significantly impaired their ability to activate plasminogen and degrade [3H]-glucosamine–labeled extracellular matrices. The migration of THP-1 monocytes through a porous membrane, in response to monocyte chemotactic protein-1, was blocked when the membranes were coated with extracellular matrix. The addition of plasminogen to the monocytes restored their ability to migrate through the matrix-coated membrane. Preincubation of THP-1 monocytes with anti–annexin II IgG inhibited (60%) their plasminogen-dependent chemotaxis through the extracellular matrix. These studies identify annexin II as a plasminogen binding site on macrophages and indicate an important role for annexin II in their invasive and degradative phenotype.
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Tajbakhsh, Amir, Petri T. Kovanen, Mahdi Rezaee, Maciej Banach, and Amirhossein Sahebkar. "Ca2+ Flux: Searching for a Role in Efferocytosis of Apoptotic Cells in Atherosclerosis." Journal of Clinical Medicine 8, no. 12 (November 21, 2019): 2047. http://dx.doi.org/10.3390/jcm8122047.
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In atherosclerosis, macrophages in the arterial wall ingest plasma lipoprotein-derived lipids and become lipid-filled foam cells with a limited lifespan. Thus, efficient removal of apoptotic foam cells by efferocytic macrophages is vital to preventing the dying foam cells from forming a large necrotic lipid core, which, otherwise, would render the atherosclerotic plaque vulnerable to rupture and would cause clinical complications. Ca2+ plays a role in macrophage migration, survival, and foam cell generation. Importantly, in efferocytic macrophages, Ca2+ induces actin polymerization, thereby promoting the formation of a phagocytic cup necessary for efferocytosis. Moreover, in the efferocytic macrophages, Ca2+ enhances the secretion of anti-inflammatory cytokines. Various Ca2+ antagonists have been seminal for the demonstration of the role of Ca2+ in the multiple steps of efferocytosis by macrophages. Moreover, in vitro and in vivo experiments and clinical investigations have revealed the capability of Ca2+ antagonists in attenuating the development of atherosclerotic plaques by interfering with the deposition of lipids in macrophages and by reducing plaque calcification. However, the regulation of cellular Ca2+ fluxes in the processes of efferocytic clearance of apoptotic foam cells and in the extracellular calcification in atherosclerosis remains unknown. Here, we attempted to unravel the molecular links between Ca2+ and efferocytosis in atherosclerosis and to evaluate cellular Ca2+ fluxes as potential treatment targets in atherosclerotic cardiovascular diseases.
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Nemmar, Abderrahim, Turan Karaca, Sumaya Beegam, Priya Yuvaraju, Javed Yasin, Naserddine Kamel Hamadi, and Badreldin H. Ali. "Prolonged Pulmonary Exposure to Diesel Exhaust Particles Exacerbates Renal Oxidative Stress, Inflammation and DNA Damage in Mice with Adenine-Induced Chronic Renal Failure." Cellular Physiology and Biochemistry 38, no. 5 (2016): 1703–13. http://dx.doi.org/10.1159/000443109.
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Background/Aims: Epidemiological evidence indicates that patients with chronic kidney diseases have increased susceptibility to adverse outcomes related to long-term exposure to particulate air pollution. However, mechanisms underlying these effects are not fully understood. Methods: Presently, we assessed the effect of prolonged exposure to diesel exhaust particles (DEP) on chronic renal failure induced by adenine (0.25% w/w in feed for 4 weeks), which is known to involve inflammation and oxidative stress. DEP (0.5m/kg) was intratracheally (i.t.) instilled every 4th day for 4 weeks (7 i.t. instillation). Four days following the last exposure to either DEP or saline (control), various renal endpoints were measured. Results: While body weight was decreased, kidney weight increased in DEP+adenine versus saline+adenine or DEP. Water intake, urine volume, relative kidney weight were significantly increased in adenine+DEP versus DEP and adenine+saline versus saline. Plasma creatinine and urea increased and creatinine clearance decreased in adenine+DEP versus DEP and adenine+saline versus saline. Tumor necrosis factor α, lipid peroxidation and reactive oxygen species were significantly increased in adenine+DEP compared with either DEP or adenine+saline. The antioxidant calase was significantly decreased in adenine+DEP compared with either adenine+saline or DEP. Notably, renal DNA damage was significantly potentiated in adenine+DEP compared with either adenine+saline or DEP. Similarly, systolic blood pressure was increased in adenine+DEP versus adenine+saline or DEP, and in DEP versus saline. Histological evaluation revealed more collagen deposition, higher number of necrotic cell counts and dilated tubules, cast formation and collapsing glomeruli in adenine+DEP versus adenine+saline or DEP. Conclusion: Prolonged pulmonary exposure to diesel exhaust particles worsen renal oxidative stress, inflammation and DNA damage in mice with adenine-induced chronic renal failure. Our data provide biological plausibility that air pollution aggravates chronic renal failure.
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Huston, Christopher D., Douglas R. Boettner, Vanessa Miller-Sims, and William A. Petri,. "Apoptotic Killing and Phagocytosis of Host Cells by the Parasite Entamoeba histolytica." Infection and Immunity 71, no. 2 (February 2003): 964–72. http://dx.doi.org/10.1128/iai.71.2.964-972.2003.
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ABSTRACT The ability of Entamoeba histolytica to kill and phagocytose host cells correlates with parasite virulence. This study addressed the role of apoptotic cell killing and host cell phosphatidylserine exposure in the subsequent phagocytosis of Jurkat T cells by E. histolytica. Ingested host cells were apoptotic, as evidenced by the activation of caspase 3 in 88% ± 3% (mean and standard deviation [SD] of the mean) of Jurkat cells engulfed by E. histolytica; ingested cells without detectable active caspase 3 were already disrupted and partially digested. That apoptotic cell killing preceded phagocytosis was supported by the demonstration that a higher percentage of amebae ingested apoptotic cells than ingested healthy cells (62% ± 7% versus 30% ± 9%, respectively [mean and SD]) (P = 0.008). E. histolytica also ingested apoptotic Jurkat cells more rapidly than necrotic control cells (8.5% ± 0.4% versus 3.5% ± 0.7%, respectively [mean and SD]) (P < 0.001). The inhibition of amebic cytotoxicity with d-galactose (which blocks the amebic Gal/GalNAc lectin) blocked the phagocytosis of healthy cells by greater than 80%, providing further evidence that apoptosis preceded engulfment. In contrast, d-galactose blocked the phagocytosis of already apoptotic cells by only 40%, implicating an additional host ligand (besides d-galactose) in amebic engulfment of apoptotic cells. The most characteristic surface change on apoptotic cells is phosphatidylserine exposure. Consistent with a role for host cell phosphatidylserine exposure in amebic ingestion of killed cells, Jurkat cell phosphatidylserine was exposed during incubation with E. histolytica (27% ± 1% [mean and SD] specific increase at 30 min) (the P value versus the control was 0.0003). Approximately 50% more amebae ingested viable Jurkat cells expressing phosphatidylserine on the outer leaflet of the plasma membrane than ingested control cells (30.3% ± 2.2% versus 19.8% ± 1.9%, respectively [mean and SD]) (P = 0.003). By analogy with phagocytic clearance during apoptosis in metazoans, amebic apoptotic host cell killing followed by phagocytosis may limit inflammation and enable amebae to evade the host immune response.
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Martin, Kyle S., Kelley M. Virgilio, Shayn M. Peirce, and Silvia S. Blemker. "Computational Modeling of Muscle Regeneration and Adaptation to Advance Muscle Tissue Regeneration Strategies." Cells Tissues Organs 202, no. 3-4 (2016): 250–66. http://dx.doi.org/10.1159/000443635.
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Skeletal muscle has an exceptional ability to regenerate and adapt following injury. Tissue engineering approaches (e.g. cell therapy, scaffolds, and pharmaceutics) aimed at enhancing or promoting muscle regeneration from severe injuries are a promising and active field of research. Computational models are beginning to advance the field by providing insight into regeneration mechanisms and therapies. In this paper, we summarize the contributions computational models have made to understanding muscle remodeling and the functional implications thereof. Next, we describe a new agent-based computational model of skeletal muscle inflammation and regeneration following acute muscle injury. Our computational model simulates the recruitment and cellular behaviors of key inflammatory cells (e.g. neutrophils and M1 and M2 macrophages) and their interactions with native muscle cells (muscle fibers, satellite stem cells, and fibroblasts) that result in the clearance of necrotic tissue and muscle fiber regeneration. We demonstrate the ability of the model to track key regeneration metrics during both unencumbered regeneration and in the case of impaired macrophage function. We also use the model to simulate regeneration enhancement when muscle is primed with inflammatory cells prior to injury, which is a putative therapeutic intervention that has not yet been investigated experimentally. Computational modeling of muscle regeneration, pursued in combination with experimental analyses, provides a quantitative framework for evaluating and predicting muscle regeneration and enables the rational design of therapeutic strategies for muscle recovery.