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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...
April 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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...
April 26, 2017: Journal of Neurotrauma
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
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
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
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
Claudia Kemper
No abstract text is available yet for this article.
September 2016: Immunology and Cell Biology
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
Peter A Ward
No abstract text is available yet for this article.
July 1, 2016: American Journal of Physiology. Renal Physiology
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
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
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
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
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
Jaco Selle, Yaw Asare, Janine Köhncke, Setareh Alampour-Rajabi, Gansuvd Shagdarsuren, Andreas Klos, Christian Weber, Joachim Jankowski, Erdenechimeg Shagdarsuren
Atherogenic processes and vascular remodelling after arterial injury are controlled and driven by a plethora of factors amongst which the activation of the complement system is pivotal. Recently, we reported a clear correlation between high expressions of the second receptor for complement anaphylatoxin C5a, the C5a receptor-like 2 (C5L2, C5aR2), with high pro-inflammatory cytokine expression in advanced human atherosclerotic plaques. This prompted us to speculate that C5aR2 might have a functional role in atherosclerosis...
October 2015: Thrombosis and Haemostasis
Gaurav Mehta, Robert I Scheinman, V Michael Holers, Nirmal K Banda
Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti-C5ab-C5 siRNA conjugate...
June 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Stavros Rafail, Ioannis Kourtzelis, Periklis G Foukas, Maciej M Markiewski, Robert A DeAngelis, Mara Guariento, Daniel Ricklin, Elizabeth A Grice, John D Lambris
Wound healing is a complex homeostatic response to injury that engages numerous cellular activities, processes, and cell-to-cell interactions. The complement system, an intricate network of proteins with important roles in immune surveillance and homeostasis, has been implicated in many physiological processes; however, its role in wound healing remains largely unexplored. In this study, we employ a murine model of excisional cutaneous wound healing and show that C3(-/-) mice exhibit accelerated early stages of wound healing...
February 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Jamison J Grailer, Fatemeh Fattahi, Rachel S Dick, Firas S Zetoune, Peter A Ward
In the early stages of sepsis, lymphocytes undergo apoptosis, resulting in lymphopenia and immunosuppression. The trigger for septic lymphopenia is unknown. Using the polymicrobial model of murine sepsis, we investigated the role of C5a receptors in septic lymphopenia. In wild-type mice, cecal ligation and puncture resulted in splenocyte apoptosis and significant lymphopenia after 3 d, which was not observed in C5aR1(-/-) or C5aR2(-/-) mice. Our data show that mouse neutrophils exposed to recombinant mouse C5a cause release of histones in a dose-dependent and time-dependent manner...
February 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Hiroko Nomaru, Kunihiko Sakumi, Atsuhisa Katogi, Yoshinori N Ohnishi, Kosuke Kajitani, Daisuke Tsuchimoto, Eric J Nestler, Yusaku Nakabeppu
The Fosb gene encodes subunits of the activator protein-1 transcription factor complex. Two mature mRNAs, Fosb and ΔFosb, encoding full-length FOSB and ΔFOSB proteins respectively, are formed by alternative splicing of Fosb mRNA. Fosb products are expressed in several brain regions. Moreover, Fosb-null mice exhibit depressive-like behaviors and adult-onset spontaneous epilepsy, demonstrating important roles in neurological and psychiatric disorders. Study of Fosb products has focused almost exclusively on neurons; their function in glial cells remains to be explored...
August 2014: Glia
Embjørg J Wollen, Yngve Sejersted, Marianne S Wright, Anna Madetko-Talowska, Miroslaw Bik-Multanowski, Przemko Kwinta, Clara-Cecilie Günther, Ståle Nygård, Else Marit Løberg, Martin B Ystgaard, Jacek J Pietrzyk, Ola D Saugstad
BACKGROUND: Supplemental oxygen used during resuscitation can be detrimental to the newborn brain. The aim was to determine how different oxygen therapies affect gene transcription in a hypoxia-reoxygenation model. METHODS: C57BL/6 mice (n = 56), postnatal day 7, were randomized either to 120 min of hypoxia 8% O2 followed by 30 min of reoxygenation with 21, 40, 60, or 100% O2, or to normoxia followed by 30 min of 21 or 100% O2. Affymetrix 750k expression array was applied with RT-PCR used for validation...
April 2014: Pediatric Research
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