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https://www.readbyqxmd.com/read/28932632/local-endothelial-complement-activation-reverses-endothelial-quiescence-enabling-t-cell-homing-and-tumor-control-during-t-cell-immunotherapy
#1
Andrea Facciabene, Francesco De Sanctis, Stefano Pierini, Edimara S Reis, Klara Balint, John Facciponte, Jens Rueter, Masahiro Kagabu, Paola Magotti, Evripidis Lanitis, Robert A DeAngelis, Ronald J Buckanovich, Wenchao C Song, John D Lambris, George Coukos
Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28931049/the-c5a-c5ar1-axis-controls-the-development-of-experimental-allergic-asthma-independent-of-lysm-expressing-pulmonary-immune-cells
#2
Anna V Wiese, Fanny Ender, Katharina M Quell, Konstantina Antoniou, Tillman Vollbrandt, Peter König, Jörg Köhl, Yves Laumonnier
C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1). Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs) and monocyte-derived DCs (moDCs) during the allergic effector phase using a floxed green fluorescent protein (GFP)-C5aR1 knock-in mouse...
2017: PloS One
https://www.readbyqxmd.com/read/28928087/complement-factor-h-in-amd-bridging-genetic-associations-and-pathobiology
#3
REVIEW
Christopher B Toomey, Lincoln V Johnson, Catherine Bowes Rickman
AMD is a complex multifactorial disease characterized in its early stages by lipoprotein accumulations in BrM, seen on fundoscopic exam as drusen, and in its late forms by neovascularization ("wet") or geographic atrophy of the RPE cell layer ("dry"). Genetic studies have strongly supported a relationship between the alternative complement cascade, in particular the common H402 variant in Complement Factor H (CFH) and development of AMD. However, the functional significance of the CFH Y402H polymorphism remains elusive...
September 16, 2017: Progress in Retinal and Eye Research
https://www.readbyqxmd.com/read/28923083/prevention-of-c5ar1-signaling-delays-microglial-inflammatory-polarization-favors-clearance-pathways-and-suppresses-cognitive-loss
#4
Michael X Hernandez, Shan Jiang, Tracy A Cole, Shu-Hui Chu, Maria I Fonseca, Melody J Fang, Lindsay A Hohsfield, Maria D Torres, Kim N Green, Rick A Wetsel, Ali Mortazavi, Andrea J Tenner
BACKGROUND: Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes...
September 18, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28921001/c3ar-and-c5ar1-act-as-key-regulators-of-human-and-mouse-%C3%AE-cell-function
#5
Patricio Atanes, Inmaculada Ruz-Maldonado, Attilio Pingitore, Ross Hawkes, Bo Liu, Min Zhao, Guo Cai Huang, Shanta J Persaud, Stefan Amisten
AIMS: Complement components 3 and 5 (C3 and C5) play essential roles in the complement system, generating C3a and C5a peptides that are best known as chemotactic and inflammatory factors. In this study we characterised islet expression of C3 and C5 complement components, and the impact of C3aR and C5aR1 activation on islet function and viability. MATERIALS AND METHODS: Human and mouse islet mRNAs encoding key elements of the complement system were quantified by qPCR and distribution of C3 and C5 proteins was determined by immunohistochemistry...
September 18, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28918528/signaling-of-the-complement-cleavage-product-anaphylatoxin-c5a-through-c5ar-cd88-contributes-to-pharmacological-hematopoietic-stem-cell-mobilization
#6
Kamila Bujko, Sylwia Rzeszotek, Kai Hoehlig, Jun Yan, Axel Vater, Mariusz Z Ratajczak
Several mechanisms have been postulated for orchestrating the mobilization of hematopoietic stem/progenitor cells (HSPCs), and we previously proposed that activation of the complement cascade plays a crucial role in the initiation and execution of the egress of HSPCs from bone marrow (BM) into peripheral blood (PB). In support of this notion, we demonstrated that mice deficient in the mannan-binding lectin (MBL) pathway, which activates the proximal part of the complement cascade, as well as mice deficient in the fifth component of the complement cascade (C5), which is part of the distal part of the complement cascade, are poor mobilizers...
September 16, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/28903945/complement-c5a-receptors-c5l2-and-c5ar-in-renal-fibrosis
#7
Ina V Martin, Annika Bohner, Peter Boor, Erdenechimeg Shagdarsuren, Ute Raffetseder, Frank Lammert, Jürgen Floege, Tammo Ostendorf, Susanne N Weber
Complement factor C5a has two known receptors, C5aR mediating pro-inflammatory effects and C5L2, a potential C5a scavenger. We previously identified C5a/C5aR signaling as a potent profibrotic pathway in the kidney. Here we tested for the first time the role of C5L2 in renal fibrosis. In unilateral ureteral obstruction (UUO)-induced kidney fibrosis, the expression of C5aR and C5L2 increased similarly and gradually as fibrosis progressed and was particularly prominent in injured dilated tubules. Genetic deficiency of either C5aR or C5L2 significantly reduced UUO-induced tubular injury...
September 13, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28894081/eculizumab-in-renal-transplantation-a-2017-update
#8
Ryszard Grenda, Magdalena Durlik
Despite ongoing progress in renal transplantation, there are still emerging challenges in this field, including consequences of ischemia-reperfusion injury (IRI), pre-existing and produced de novo anti-HLA donor-specific antibodies (DSA), and acute/chronic humoral rejection (AMR), as well as the recurrence of atypical hemolytic-uremic syndrome (aHUS) in genetically predisposed patients. All these conditions are related to the prominent role of the complement system and are deleterious to the fate of the renal graft...
September 12, 2017: Annals of Transplantation: Quarterly of the Polish Transplantation Society
https://www.readbyqxmd.com/read/28876118/-effects-of-complement-c5a-inhibitor-therapy-in-animal-models-of-non-occlusive-mesenteric-ischemia
#9
Miklós Nógrády, Gabriella Varga, Szilárd Szűcs, József Kaszaki, Mihály Boros, Dániel Érces
INTRODUCTION: Non-occlusive mesenteric ischemia (NOMI) develops without anatomical causes. Early diagnosis is challenging and treatments are of questionable effectiveness. We investigated the role of complement activation in the pathophysiology of NOMI in animal models through the inhibition of complement C5a. MATERIALS AND METHODS: 60-min partial aortic occlusion (PAO; abdominal aorta, proximal to celiac trunk; mean arterial pressure: 30-40 mmHg) was established in Sprague-Dawley rats (n = 28) and 60-min cardiac tamponade in minipigs (n = 19; mean arterial pressure: 40-50 mmHg) to observe short- and long-term circulatory and inflammatory consequences of NOMI...
September 2017: Magyar Sebészet
https://www.readbyqxmd.com/read/28864475/monitoring-c5ar2-expression-using-a-floxed-tdtomato-c5ar2-knock-in-mouse
#10
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...
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28860952/yersinia-enterocolitica-exploits-signal-crosstalk-between-complement-5a-receptor-and-toll-like-receptor-1-2-and-4-to-avoid-the-bacterial-clearance-in-m-cells
#11
Sae-Hae Kim, Yong-Suk Jang
In the intestinal mucosal surface, microfold cells (M cells) are the representative gateway for the uptake of luminal antigens. At the same time, M cells are the primary infection site for pathogens invading mucosal surface for their infection. Although it is well recognized that many mucosal pathogens exploit the M cells for their infection, the mechanism to infect M cells utilized by pathogens is not clearly understood yet. In this study, we found that M cells expressing complement 5a (C5a) receptor (C5aR) also express Toll-like receptor (TLR) 1/2 and TLR4...
August 2017: Immune Network
https://www.readbyqxmd.com/read/28846569/effects-of-prior-psychosocial-trauma-on-subsequent-immune-response-after-experimental-thorax-trauma
#12
Dominik Langgartner, Annette Palmer, Anne Rittlinger, Stefan O Reber, Markus Huber-Lang
Overshooting inflammation during the early phase after blunt thorax trauma promotes the development of acute respiratory distress syndrome, multiple organ failure and subsequent mortality. Given that individuals diagnosed with stress-related disorders are characterized by chronic low-grade inflammation, we hypothesize that "psychosocial traumatic preload" poses a risk factor for the above mentioned complications following thorax trauma.Here, we employed the chronic subordinate colony housing (CSC) paradigm to induce "psychosocial traumatic preload" and systemic low-grade immune activation in male mice, indicated by elevated plasma concentrations of different inflammatory mediators...
August 25, 2017: Shock
https://www.readbyqxmd.com/read/28832655/complement-inhibition-attenuates-acute-kidney-injury-after-ischemia-reperfusion-and-limits-progression-to-renal-fibrosis-in-mice
#13
Juan S Danobeitia, Martynas Ziemelis, Xiaobo Ma, Laura J Zitur, Tiffany Zens, Peter J Chlebeck, Edwin S Van Amersfoort, Luis A Fernandez
The complement system is an essential component of innate immunity and plays a major role in the pathogenesis of ischemia-reperfusion injury (IRI). In this study, we investigated the impact of human C1-inhibitor (C1INH) on the early inflammatory response to IRI and the subsequent progression to fibrosis in mice. We evaluated structural damage, renal function, acute inflammatory response, progression to fibrosis and overall survival at 90-days post-injury. Animals receiving C1INH prior to reperfusion had a significant improvement in survival rate along with superior renal function when compared to vehicle (PBS) treated counterparts...
2017: PloS One
https://www.readbyqxmd.com/read/28821630/il-17a-deficiency-mitigates-bleomycin-induced-complement-activation-during-lung-fibrosis
#14
Ellyse Cipolla, Amanda J Fisher, Hongmei Gu, Elizabeth A Mickler, Manisha Agarwal, Carol A Wilke, Kevin K Kim, Bethany B Moore, Ragini Vittal
Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3, and GPCR kinase isoform 5), cytokines (IL8, -6, and -1B), and cytokine ligands (CXCL1, -2, -3, -5, -6, and -16)...
August 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28808141/a-critical-role-for-plasma-kallikrein-in-the-pathogenesis-of-autoantibody-induced-arthritis
#15
Aizhen Yang, Junsong Zhou, Bo Wang, Jihong Dai, Robert W Colman, Wenchao Song, Yi Wu
The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis...
August 14, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28806402/multi-functional-mechanisms-of-immune-evasion-by-the-streptococcal-complement-inhibitor-c5a-peptidase
#16
Nicola N Lynskey, Mark Reglinski, Damien Calay, Matthew K Siggins, Justin C Mason, Marina Botto, Shiranee Sriskandan
The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase...
August 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28782758/mechanism-of-c5a-induced-immunologic-derangement-in-sepsis
#17
Ruonan Xu, Fang Lin, Chunmei Bao, Fu-Sheng Wang
No abstract text is available yet for this article.
September 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28769928/anaphylatoxin-c5a-regulates-6-sulfo-lacnac-dendritic-cell-function-in-human-through-crosstalk-with-toll-like-receptor-induced-creb-signaling
#18
Anouk Zaal, Miranda Dieker, Manon Oudenampsen, Annelies W Turksma, Suzanne N Lissenberg-Thunnissen, Diana Wouters, S Marieke van Ham, Anja Ten Brinke
Activation of antigen-presenting dendritic cells (DCs) and the complement system are essential early events in the immune defense against invading pathogens. Recently, we and others demonstrated immunological crosstalk between signaling from receptors recognizing complement activation products and PAMPs on DCs. This affects DC effector function, as demonstrated by the finding that C5a prevents induction of pro-inflammatory cytokines by toll-like receptor (TLR) ligands in human monocyte-derived DCs (moDCs). Here, we demonstrate that this regulatory crosstalk is specifically important in 6-sulfo LacNAc dendritic cells (slanDCs), the most pro-inflammatory DC subset found in human...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28745692/-changes-in-the-complement-system-in-membranoproliferative-glomerulonephritis
#19
V A Yurova, L A Bobrova, N L Kozlovskaya, Yu V Korotchaeva, A G Serova, L V Kozlov, S S Andina, K A Demyanova, A M Kuchieva, S V Roshchupkina
AIM: To compare the clinical manifestations membranoproliferative glomerulonephritis (MPGN) in its idiopathic variant, lupus nephritis (LN), and C3 glomerulopathy (C3-GP), by comparing them with changes in the complement system. SUBJECTS AND METHODS: The clinic of nephrology followed up 42 patients with different types of MPGN in 2013 to 2015. The study included 35 patients divided into 3 groups: 1) 8 patients with C3-GP, 2) 13 with idiopathic MPGN; 3) 14 with Class IV LN...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28733463/tlr4-and-c5ar-crosstalk-in-dendritic-cells-induces-a-core-regulatory-network-of-rsk2-pi3k%C3%AE-sgk1-and-foxo-transcription-factors
#20
Anouk Zaal, Benjamin Nota, Kat S Moore, Miranda Dieker, S Marieke van Ham, Anja Ten Brinke
Crosstalk between complement component 5a receptors (C5aRs) and TLRs in dendritic cells (DCs) occurs upon pathogen invasion; however, studies on C5aR and TLR crosstalk mainly focused on the modulating effect of C5a on TLR-induced cytokine production. To elucidate the breadth of C5aR and TLR4 crosstalk, the effect of simultaneous treatment with C5a and LPS was investigated in human monocyte-derived DCs (moDCs) 2 h after stimulation using whole transcriptome sequencing analysis. Although the effect of C5a on hallmark genes defining TLR4-induced DC maturation was limited at this time point, RNA sequencing analysis revealed a great variety of novel C5a targets, of which many interfere with TLR4-mediated immune activation...
July 21, 2017: Journal of Leukocyte Biology
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