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C5aR2

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https://www.readbyqxmd.com/read/29070810/complement-receptors-c5ar1-and-c5ar2-act-differentially-during-the-early-immune-response-after-bone-fracture-but-are-similarly-involved-in-bone-repair
#1
Anna Kovtun, Stephanie Bergdolt, Yvonne Hägele, Rebekka Matthes, John D Lambris, Markus Huber-Lang, Anita Ignatius
Severely injured patients frequently suffer compromised fracture healing because of systemic post-traumatic inflammation. An important trigger of the posttraumatic immune response is the complement anaphylatoxin C5a, which acts via two receptors, C5aR1 and C5aR2, expressed on immune and bone cells. The blockade of C5a-mediated inflammation during the early inflammatory phase was demonstrated to improve fracture healing after severe injury. However, the distinct roles of the two complement receptors C5aR1 and C5aR2 in bone has to date not been studied...
October 25, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28952876/structure-and-characterization-of-a-high-affinity-c5a-monoclonal-antibody-that-blocks-binding-to-c5ar1-and-c5ar2-receptors
#2
Caroline S Colley, Bojana Popovic, Sudharsan Sridharan, Judit E Debreczeni, David Hargeaves, Michael Fung, Ling-Ling An, Bryan Edwards, Joanne Arnold, Elizabeth England, Laura Eghobamien, Ulf Sivars, Liz Flavell, Jonathan Renshaw, Kate Wickson, Paul Warrener, Jingying Zha, Jessica Bonnell, Rob Woods, Trevor Wilkinson, Claire Dobson, Tristan J Vaughan
C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors...
September 27, 2017: MAbs
https://www.readbyqxmd.com/read/28864475/monitoring-c5ar2-expression-using-a-floxed-tdtomato-c5ar2-knock-in-mouse
#3
Christian M Karsten, Anna V Wiese, Fabian Mey, Julia Figge, Trent M Woodruff, Tom Reuter, Olga Scurtu, Anna Kordowski, Larissa N Almeida, Daria Briukhovetska, Katharina M Quell, Jing Sun, Fanny Ender, Inken Schmudde, Tillman Vollbrandt, Yves Laumonnier, Jörg Köhl
The biological significance of C5a receptor [(C5aR)2/C5L2], a seven-transmembrane receptor binding C5a and C5adesArg, remains ill-defined. Specific ligation of C5aR2 inhibits C5a-induced ERK1/2 activation, strengthening the view that C5aR2 regulates C5aR1-mediated effector functions. Although C5aR2 and C5aR1 are often coexpressed, a detailed picture of C5aR2 expression in murine cells and tissues is still lacking. To close this gap, we generated a floxed tandem dye (td)Tomato-C5aR2 knock-in mouse that we used to track C5aR2 expression in tissue-residing and circulating immune cells...
November 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28706957/the-controversial-c5a-receptor-c5ar2-its-role-in-health-and-disease
#4
REVIEW
Ting Zhang, Malgorzata A Garstka, Ke Li
After the discovery of the C5a receptor C5aR1, C5aR2 is the second receptor found to bind C5a and its des-arginine form. As a heptahelical G protein-coupled receptor but devoid of the intracellular Gα signal, C5aR2 is special and confusing. Ramifications and controversies about C5aR2 are under debate since its identification, from putative ligands and cellular localization to intracellular signals and pathological roles in inflammation and immunity. The ruleless and even conflicting pro- or anti-inflammatory role of C5aR2 in animal models of diverse diseases makes one bewildered...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28600003/novel-insights-into-the-expression-pattern-of-anaphylatoxin-receptors-in-mice-and-men
#5
REVIEW
Yves Laumonnier, Christian M Karsten, Jörg Köhl
The anaphylatoxins (AT) C3a and C5a play important roles as mediators of inflammation. Further, they regulate and control multiple innate and adaptive immune responses through binding and activation of their cognate G protein-coupled receptors, i.e. C3a receptor (C3aR), C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2), although the latter lacks important sequence motifs for G protein-coupling. Based on their pleiotropic functions, they contribute not only to tissue homeostasis but drive, perpetuate and resolve immune responses in many inflammatory diseases including infections, malignancies, autoimmune as well as allergic diseases...
September 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28576324/new-concepts-on-the-therapeutic-control-of-complement-anaphylatoxin-receptors
#6
REVIEW
Owen A Hawksworth, Xaria X Li, Liam G Coulthard, Ernst J Wolvetang, Trent M Woodruff
The complement system is a pivotal driver of innate immunity, coordinating the host response to protect against pathogens. At the heart of the complement response lie the active fragments, C3a and C5a, acting through their specific receptors, C3aR, C5aR1, and C5aR2, to direct the cellular response to inflammation. Their potent function however, places them at risk of damaging the host, with aberrant C3a and C5a signaling activity linked to a wide range of disorders of inflammatory, autoimmune, and neurodegenerative etiologies...
September 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28396344/critical-role-for-complement-receptor-c5ar2-in-the-pathogenesis-of-renal-ischemia-reperfusion-injury
#7
Felix Poppelaars, Maaike B van Werkhoven, Juha Kotimaa, Zwanida J Veldhuis, Albertina Ausema, Stefan G M Broeren, Jeffrey Damman, Julia C Hempel, Henri G D Leuvenink, Mohamed R Daha, Willem J van Son, Cees van Kooten, Ronald P van Os, Jan-Luuk Hillebrands, Marc A Seelen
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1(-/-), and C5aR2(-/-) mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury...
July 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28173736/the-alternative-receptor-for-complement-component-5a-c5ar2-conveys-neuroprotection-in-traumatic-spinal-cord-injury
#8
Patrick J C Biggins, Faith H Brennan, Stephen M Taylor, Trent M Woodruff, Marc J Ruitenberg
This study investigated the role of the alternative receptor for complement activation fragment C5a, C5aR2, in secondary inflammatory pathology after contusive spinal cord injury (SCI) in mice. C5ar2(-/-) mice exhibited decreased intraparenchymal tumor necrosis factor alpha and interleukin-6 acutely post-injury, but these reductions did not translate into improved outcomes. We show that loss of C5aR2 leads to increased lesion volumes, reduced myelin sparing, and significantly worsened recovery from SCI in C5ar2(-/-) animals compared to wild-type (WT) controls...
June 15, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/27931779/complement-and-sepsis-induced-heart-dysfunction
#9
REVIEW
Fatemeh Fattahi, Peter A Ward
It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after "recovery" from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis...
April 2017: Molecular Immunology
https://www.readbyqxmd.com/read/27624143/complement-c5a-induces-pd-l1-expression-and-acts-in-synergy-with-lps-through-erk1-2-and-jnk-signaling-pathways
#10
Ling-Ling An, Jacob V Gorman, Geoffrey Stephens, Bonnie Swerdlow, Paul Warrener, Jessica Bonnell, Tomas Mustelin, Michael Fung, Roland Kolbeck
Severe bacterial infection results in both uncontrolled inflammation and immune suppression in septic patients. Although there is ample evidence that complement activation provokes overwhelming pro-inflammatory responses, whether or not it plays a role in immune suppression in this case is unclear. Here, we identify that complement C5a directly participates in negative regulation of immune responses to bacteria-induced inflammation in an ex vivo model of human whole blood. Challenge of whole blood with heat-killed Pseudomonas aeruginosa induces PD-L1 expression on monocytes and the production of IL-10 and TGF-β, which we show to be inhibited by C5a blockade...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27543123/complement-induced-activation-of-the-cardiac-nlrp3-inflammasome-in-sepsis
#11
Miriam Kalbitz, Fatemeh Fattahi, Jamison J Grailer, Lawrence Jajou, Elizabeth A Malan, Firas S Zetoune, Markus Huber-Lang, Mark W Russell, Peter A Ward
Cardiac dysfunction develops during sepsis in humans and rodents. In the model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we investigated the role of the NLRP3 inflammasome in the heart. Mouse heart homogenates from sham-procedure mice contained high mRNA levels of NLRP3 and IL-1β. Using the inflammasome protocol, exposure of cardiomyocytes (CMs) to LPS followed by ATP or nigericin caused release of mature IL-1β. Immunostaining of left ventricular frozen sections before and 8 h after CLP revealed the presence of NLRP3 and IL-1β proteins in CMs...
December 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27521340/complement-destabilizes-cardiomyocyte-function-in-vivo-after-polymicrobial-sepsis-and-in-vitro
#12
Miriam Kalbitz, Fatemeh Fattahi, Todd J Herron, Jamison J Grailer, Lawrence Jajou, Hope Lu, Markus Huber-Lang, Firas S Zetoune, J Vidya Sarma, Sharlene M Day, Mark W Russell, José Jalife, Peter A Ward
There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca(2+) concentrations during diastole, together with the appearance of spontaneous Ca(2+) transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na(+)/K(+)-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca(2+) concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na(+)/Ca(2+) exchanger...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27457155/targeting-the-dark-horse-of-complement-the-first-generation-of-functionally-selective-c5ar2-ligands
#13
Claudia Kemper
No abstract text is available yet for this article.
September 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27313051/t-helper-1-immunity-requires-complement-driven-nlrp3-inflammasome-activity-in-cd4%C3%A2-%C2%BA-t-cells
#14
Giuseppina Arbore, Erin E West, Rosanne Spolski, Avril A B Robertson, Andreas Klos, Claudia Rheinheimer, Pavel Dutow, Trent M Woodruff, Zu Xi Yu, Luke A O'Neill, Rebecca C Coll, Alan Sher, Warren J Leonard, Jörg Köhl, Pete Monk, Matthew A Cooper, Matthew Arno, Behdad Afzali, Helen J Lachmann, Andrew P Cope, Katrin D Mayer-Barber, Claudia Kemper
The NLRP3 inflammasome controls interleukin-1β maturation in antigen-presenting cells, but a direct role for NLRP3 in human adaptive immune cells has not been described. We found that the NLRP3 inflammasome assembles in human CD4(+) T cells and initiates caspase-1-dependent interleukin-1β secretion, thereby promoting interferon-γ production and T helper 1 (T(H)1) differentiation in an autocrine fashion. NLRP3 assembly requires intracellular C5 activation and stimulation of C5a receptor 1 (C5aR1), which is negatively regulated by surface-expressed C5aR2...
June 17, 2016: Science
https://www.readbyqxmd.com/read/27147673/complement-an-unfinished-symphony
#15
EDITORIAL
Peter A Ward
No abstract text is available yet for this article.
July 1, 2016: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27108698/discovery-of-functionally-selective-c5ar2-ligands-novel-modulators-of-c5a-signalling
#16
Daniel E Croker, Peter N Monk, Reena Halai, Geraldine Kaeslin, Zoe Schofield, Mike Cl Wu, Richard J Clark, Mark At Blaskovich, Dimitrios Morikis, Christodoulos A Floudas, Matthew A Cooper, Trent M Woodruff
The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function...
September 2016: Immunology and Cell Biology
https://www.readbyqxmd.com/read/27081768/differential-capacity-for-complement-receptor-mediated-immune-evasion-by-porphyromonas-gingivalis-depending-on-the-type-of-innate-leukocyte
#17
G Hajishengallis, J L Krauss, R Jotwani, J D Lambris
The complement system plays a central role in immunity and inflammation, although certain pathogens can exploit complement to undermine protective immunity. In this context, the periodontal keystone pathogen Porphyromonas gingivalis was previously shown by our group to evade killing by neutrophils or macrophages through exploitation of complement C5a receptor 1 (C5aR1) and complement receptor 3 (CR3). Here, we examined whether P. gingivalis uses complement receptors to also subvert killing by dendritic cells...
April 2017: Molecular Oral Microbiology
https://www.readbyqxmd.com/read/26512700/differential-contributions-of-the-complement-anaphylotoxin-receptors-c5ar1-and-c5ar2-to-the-early-innate-immune-response-against-staphylococcus-aureus-infection
#18
Sarah A Horst, Andreas Itzek, Andreas Klos, Andreas Beineke, Eva Medina
The complement anaphylatoxin C5a contributes to host defense against Staphylococcus aureus. In this study, we investigated the functional role of the two known C5a receptors, C5aR1 and C5aR2, in the host response to S. aureus. We found that C5aR1(-/)(-) mice exhibited greater susceptibility to S. aureus bloodstream infection than wild type and C5aR2(-/)(-) mice, as demonstrated by the significantly higher bacterial loads in the kidneys and heart at 24 h of infection, and by the higher levels of inflammatory IL-6 in serum...
2015: Pathogens
https://www.readbyqxmd.com/read/26283482/the-novel-receptor-c5ar2-is-required-for-c5a-mediated-human-mast-cell-adhesion-migration-and-proinflammatory-mediator-production
#19
Priyanka Pundir, Clayton A MacDonald, Marianna Kulka
C5a generated during complement activation possesses proinflammatory and immunoregulatory properties critical for the development and modulation of allergic immune responses. In immune cells, C5a mediates its effects through binding to two G protein-coupled receptors, C5aR1 and C5aR2. Mast cells are key effectors in allergic reactions, and decades of research have suggested that the majority of C5a effects on mast cells are mediated through C5aR1, whereas the expression and function of C5aR2 have not been explored...
September 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/26091719/differential-interaction-of-the-staphylococcal-toxins-panton-valentine-leukocidin-and-%C3%AE-hemolysin-cb-with-human-c5a-receptors
#20
András N Spaan, Ariën Schiepers, Carla J C de Haas, Davy D J J van Hooijdonk, Cédric Badiou, Hugues Contamin, François Vandenesch, Gérard Lina, Norma P Gerard, Craig Gerard, Kok P M van Kessel, Thomas Henry, Jos A G van Strijp
Staphylococcus aureus is well adapted to the human host. Evasion of the host phagocyte response is critical for successful infection. The staphylococcal bicomponent pore-forming toxins Panton-Valentine leukocidin LukSF-PV (PVL) and γ-hemolysin CB (HlgCB) target human phagocytes through interaction with the complement receptors C5aR1 and C5aR2. Currently, the apparent redundancy of both toxins cannot be adequately addressed in experimental models of infection because mice are resistant to PVL and HlgCB. The molecular basis for species specificity of the two toxins in animal models is not completely understood...
August 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
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