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Ravichandran kodi

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
Michael R Elliott, Kodi S Ravichandran
The phagocytic clearance of dying cells in a tissue is a highly orchestrated series of intercellular events coordinated by a complex signaling network. Recent data from genetic, biochemical, and live-imaging approaches have greatly enhanced our understanding of the dynamics of cell clearance and how the process is orchestrated at the cellular and tissue levels. We discuss how networks regulating apoptotic cell clearance are integrated to enable a rapid, efficient, and high-capacity clearance system within tissues...
July 25, 2016: Developmental Cell
Amiram Ariel, Kodi S Ravichandran
Apoptotic leukocyte clearance is a hallmark of the resolution of inflammation and is a central fate-determining event for macrophages. The directional migration of motile phagocytes toward cellular corpses and the subsequent engulfment are tightly regulated, and the exciting molecular mechanisms for these complex steps are actively under investigation. In this issue Angsana et al. [Eur. J. Immunol. 2016. 46: 1592-1599.] report that the chemokine receptor CXCR4 is upregulated on murine and human macrophages following the engulfment of apoptotic cells, or following exposure to the pro-resolving nucleotide adenosine...
July 2016: European Journal of Immunology
Klaus Ley, Akula Bala Pramod, Michael Croft, Kodi S Ravichandran, Jenny P Ting
Macrophages are central to both innate and adaptive immunity. With few exceptions, macrophages are the first cells that sense trouble and respond to disturbances in almost all tissues and organs. They sense their environment, inhibit or kill pathogens, take up apoptotic and necrotic cells, heal tissue damage, and present antigens to T cells. Although the origins (yolk sac versus monocyte-derived) and phenotypes (functions, gene expression profiles, surface markers) of macrophages vary between tissues, they have many receptors in common that are specific to one or a few molecular species...
2016: Frontiers in Immunology
Chang Sup Lee, Kristen K Penberthy, Karen M Wheeler, Ignacio J Juncadella, Peter Vandenabeele, Jeffrey J Lysiak, Kodi S Ravichandran
Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated. Consistent with this, BAI1-deficient mice had more pronounced colitis and lower survival, with many uncleared apoptotic corpses and inflammatory cytokines within the colonic epithelium...
April 19, 2016: Immunity
Emily A Billings, Chang Sup Lee, Katherine A Owen, Ryan S D'Souza, Kodi S Ravichandran, James E Casanova
The detection of microbes and initiation of an innate immune response occur through pattern recognition receptors (PRRs), which are critical for the production of inflammatory cytokines and activation of the cellular microbicidal machinery. In particular, the production of reactive oxygen species (ROS) by the NADPH oxidase complex is a critical component of the macrophage bactericidal machinery. We previously characterized brain-specific angiogenesis inhibitor 1 (BAI1), a member of the adhesion family of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs), as a PRR that mediates the selective phagocytic uptake of Gram-negative bacteria by macrophages...
February 2, 2016: Science Signaling
Kristen K Penberthy, Kodi S Ravichandran
Phosphatidylserine recognition receptors are a highly diverse set of receptors grouped by their ability to recognize the 'eat-me' signal phosphatidylserine on apoptotic cells. Most of the phosphatidylserine recognition receptors dampen inflammation by inducing the production of anti-inflammatory mediators during the phagocytosis of apoptotic corpses. However, many phosphatidylserine receptors are also capable of recognizing other ligands, with some receptors being categorized as scavenger receptors. It is now appreciated that these receptors can elicit different downstream events for particular ligands...
January 2016: Immunological Reviews
Sanja Arandjelovic, Kodi S Ravichandran
Human bodies collectively turn over about 200 billion to 300 billion cells every day. Such turnover is an integral part of embryonic and postnatal development, as well as routine tissue homeostasis. This process involves the induction of programmed cell death in specific cells within the tissues and the specific recognition and removal of dying cells by a clearance 'crew' composed of professional, non-professional and specialized phagocytes. In the past few years, considerable progress has been made in identifying many features of apoptotic cell clearance...
September 2015: Nature Immunology
Alexander W Lohman, Igor L Leskov, Joshua T Butcher, Scott R Johnstone, Tara A Stokes, Daniela Begandt, Leon J DeLalio, Angela K Best, Silvia Penuela, Norbert Leitinger, Kodi S Ravichandran, Karen Y Stokes, Brant E Isakson
Inflammatory cell recruitment to local sites of tissue injury and/or infection is controlled by a plethora of signalling processes influencing cell-to-cell interactions between the vascular endothelial cells (ECs) in post-capillary venules and circulating leukocytes. Recently, ATP-sensitive P2Y purinergic receptors have emerged as downstream regulators of EC activation in vascular inflammation. However, the mechanism(s) regulating cellular ATP release in this response remains elusive. Here we report that the ATP-release channel Pannexin1 (Panx1) opens downstream of EC activation by TNF-α...
2015: Nature Communications
Aaron M Fond, Chang Sup Lee, Ira G Schulman, Robert S Kiss, Kodi S Ravichandran
Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane-initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein...
July 1, 2015: Journal of Clinical Investigation
Georgia K Atkin-Smith, Rochelle Tixeira, Stephanie Paone, Suresh Mathivanan, Christine Collins, Michael Liem, Katharine J Goodall, Kodi S Ravichandran, Mark D Hulett, Ivan K H Poon
Disassembly of apoptotic cells into smaller fragments (a form of extracellular vesicle called apoptotic bodies) can facilitate removal of apoptotic debris and intercellular communication. However, the mechanism underpinning this process is unclear. While observing monocytes undergoing apoptosis by time-lapse microscopy, we discovered a new type of membrane protrusion that resembles a 'beads-on-a-string' structure. Strikingly, the 'beads' are frequently sheared off the 'string' to form apoptotic bodies. Generation of apoptotic bodies via this mechanism can facilitate a sorting process and results in the exclusion of nuclear contents from apoptotic bodies...
2015: Nature Communications
Amelia E Hochreiter-Hufford, Sanja Arandjelovic, Kodi S Ravichandran
The fusion of myoblasts, the skeletal muscle progenitors, is critical for skeletal muscle formation, function, and repair after muscle injury. Recognition of the phospholipid phosphatidylserine (PtdSer) exposed on certain myoblasts is required during fusion into multinuclear myofibers. Cell surface exposure of PtdSer is also a feature of cells dying through the process of apoptosis. Here, we describe the use of PtdSer exposing apoptotic cells as stimulators of myoblast fusion.
2015: Methods in Molecular Biology
Paul C Trampont, Li Zhang, Amber J Giles, Scott F Walk, Jing J Gu, Ann Marie Pendergast, Kodi S Ravichandran
Signaling via the pre-T-cell receptor (pre-TCR), along with associated signals from Notch and chemokine receptors, regulates the β-selection checkpoint that operates on CD4(-) CD8(-) doubly negative (DN) thymocytes. Since many hematopoietic malignancies arise at the immature developmental stages of lymphocytes, understanding the signal integration and how specific signaling molecules and distal transcription factors regulate cellular outcomes is of importance. Here, a series of molecular and genetic approaches revealed that the ShcA adapter protein critically influences proliferation and differentiation during β-selection...
April 2015: Molecular and Cellular Biology
Marie Billaud, Yu-Hsin Chiu, Alexander W Lohman, Thibaud Parpaite, Joshua T Butcher, Stephanie M Mutchler, Leon J DeLalio, Mykhaylo V Artamonov, Joanna K Sandilos, Angela K Best, Avril V Somlyo, Roger J Thompson, Thu H Le, Kodi S Ravichandran, Douglas A Bayliss, Brant E Isakson
Both purinergic signaling through nucleotides such as ATP (adenosine 5'-triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vasoconstriction mediated by the α1 adrenoreceptor (α1AR), whereas vasoconstriction in response to serotonin or endothelin-1 was independent of Panx1...
February 17, 2015: Science Signaling
Edward C Stites, Paul C Trampont, Lisa B Haney, Scott F Walk, Kodi S Ravichandran
Cancer develops after the acquisition of a collection of mutations that together create the cancer phenotype. How collections of mutations work together within a cell and whether there is selection for certain combinations of mutations are not well understood. We investigated this problem with a mathematical model of the Ras signaling network, including a computational random mutagenesis. Modeling and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the effects of other Ras pathway mutations, including weakly activating, noncanonical Ras mutants...
January 15, 2015: Cell Reports
Monica W Buckley, Paul C Trampont, Sanja Arandjelovic, Aaron M Fond, Ignacio J Juncadella, Kodi S Ravichandran
T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the β-selection stage, as well as via the TCR for selection from the CD4(+)CD8(+) double-positive stage to the CD4 or CD8 single-positive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the β-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed...
February 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Kristen K Penberthy, Ignacio J Juncadella, Kodi S Ravichandran
Insult or injury to the lung epithelial cells from pathogens, pollutants, and allergens can initiate the process of apoptotic cell death. Although "Creola bodies," which are clusters of uncleared, apoptotic, epithelial cells, have been seen in the sputum of patients with asthma, the clearance of these dying epithelial cells and the consequence of failed clearance in the airway have not been directly addressed. We have observed that bronchial epithelial cells efficiently engulf their apoptotic neighbors and produce antiinflammatory cytokines when engulfing apoptotic cells...
December 2014: Annals of the American Thoracic Society
Frances L Byrne, Ivan K H Poon, Susan C Modesitt, Jose L Tomsig, Jenny D Y Chow, Marin E Healy, William D Baker, Kristen A Atkins, Johnathan M Lancaster, Douglas C Marchion, Kelle H Moley, Kodi S Ravichandran, Jill K Slack-Davis, Kyle L Hoehn
Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells...
October 15, 2014: Cancer Research
Monica W Buckley, Sanja Arandjelovic, Paul C Trampont, Taeg S Kim, Thomas J Braciale, Kodi S Ravichandran
T cell development and activation are highly regulated processes, and their proper execution is important for a competent immune system. Shc SH2-domain binding protein-1 (Shcbp1) is an evolutionarily conserved protein that binds to the adaptor protein ShcA. Studies in Drosophila and in cell lines have strongly linked Shcbp1 to cell proliferation, embryonic development, growth factor signaling, and tumorigenesis. Here we show that Shcbp1 expression is strikingly upregulated during the β-selection checkpoint in thymocytes, and that its expression tightly correlates with proliferative stages of T cell development...
2014: PloS One
Chelsea S Sullivan, Jami L Scheib, Zhong Ma, Rajan P Dang, Johanna M Schafer, Francis E Hickman, Frances M Brodsky, Kodi S Ravichandran, Bruce D Carter
During the development of the peripheral nervous system, the large number of apoptotic neurons generated are phagocytosed by glial precursor cells. This clearance is mediated, in part, through the mammalian engulfment receptor Jedi-1. However, the mechanisms by which Jedi-1 mediates phagocytosis are poorly understood. Here we demonstrate that Jedi-1 associates with GULP, the mammalian homologue of CED-6, an adaptor protein required for phagocytosis mediated by the nematode engulfment receptor CED-1. Silencing GULP or mutating the NPXY motif in Jedi-1, which is required for GULP binding, prevents Jedi-1-mediated phagocytosis...
June 15, 2014: Molecular Biology of the Cell
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