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Andrew F. Ducruet - One of the best experts on this subject based on the ideXlab platform.
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abstract p732 genetic ablation of endothelial C3a Receptor confers cerebrovascular protection independent of the dynamics of reperfusion in stroke
Stroke, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Nasrul Hoda, Sara Bowen, Michael F Waters, Andrew F. DucruetAbstract:Background: Stroke enhances endothelial C3a Receptor (C3aREnd) expression and humoral levels of C3a which is further exacerbated by intravenous thrombolysis (IVT). Therefore, it is critical to inve...
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complement C3a Receptor mediated vascular dysfunction a complex interplay between aging and neurodegeneration
Journal of Clinical Investigation, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Kanchan Bhatia, Andrew F. DucruetAbstract:Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a Receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR-mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1-/-) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.
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Abstract P732: Genetic Ablation of Endothelial C3a-Receptor Confers Cerebrovascular Protection Independent of the Dynamics of Reperfusion in Stroke
Stroke, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Nasrul Hoda, Sara Bowen, Michael F Waters, Andrew F. DucruetAbstract:Background: Stroke enhances endothelial C3a Receptor (C3aR End ) expression and humoral levels of C3a which is further exacerbated by intravenous thrombolysis (IVT). Therefore, it is critical to investigate the role of C3aR End in post-stroke neurovascular injury. Hypothesis: Genetic depletion of C3aR is vasculoprotective in stroke. Methods: Using a loxP - Cre approach (C3aR Flox/Flox xCdh5 Cre ), we generated mice conditionally deficient or sufficient in C3aR End (C3aR End-/- or C3aR End+/+ ), and subjected males (6±0.5-mo old) to thrombotic stroke (TS). Cerebral blood flow (CBF), behavioral outcomes, infarct volume, blood brain barrier (BBB) leakage, brain hemoglobin (Hb) content, brain tissue oxygen (PbtO 2 ) , neutrophil polarization ( Proinflammatory N1: Li6G + CD206 - vs. Antiinflammatory N2: Li6G + CD206 + ) and their brain infiltration were analyzed. P<0.05 was considered statistically significant. Results: TS resulted in similar degree of cerebral ischemia in both groups (N=10/gp); however, CBF, behavior, and infarct volume were significantly improved in C3aR End-/- vs. C3aR End+/+ mice at 72h post-TS. BBB-leakage and brain-Hb at 72h were less in C3aR End-/- vs. C3aR End+/+ mice but this did not meet significance (N=5/gp). Interestingly, C3a infusion 3h post-TS significantly enhanced BBB-leakage and brain-Hb in C3aR End+/+ but not in C3aR End-/- mice at 72h (N=5/gp), demonstrating that C3a in conjunction with C3aR End exacerbates neurovascular injury in TS. Moreover, late-IVT at 4h post-TS (2 mg/kgbwt; N=8/gp) significantly enhanced PbtO 2 in C3aR End-/- vs. C3aR End+/+ mice when assessed at 6h. Finally, C3aR deficiency significantly enhanced the N2/N1 ratio relative to the C3aR sufficient group at 24h post-TS (N=3/gp); thus inducing an anti-inflammatory effect and reduced neutrophil brain infiltration. Conclusion: C3aR End plays a critical role in stroke injury. Future studies targeting brain specific C3aR End are warranted.
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the role of complement C3a Receptor in stroke
Neuromolecular Medicine, 2019Co-Authors: Saif Ahmad, Adam Kindelin, Kanchan Bhatia, Andrew F. DucruetAbstract:The complement system is a key regulator of the innate immune response against diseased tissue that functions across multiple organ systems. Dysregulation of complement contributes to the pathogenesis of a number of neurological diseases including stroke. The C3a anaphylatoxin, via its cognate C3a Receptor (C3aR), mediates inflammation by promoting breakdown of the blood-brain barrier and the massive infiltration of leukocytes into ischemic brain in experimental stroke models. Studies utilizing complement deficient mice as well as pharmacologic C3aR antagonists have shown a reduction in tissue injury and mortality in murine stroke models. The development of tissue-specific C3aR knockout mice and more specific C3aR antagonists is warranted to facilitate our understanding of the role of the C3aR in brain ischemia with the ultimate goal of clinical translation of therapies targeting C3aR in stroke patients.
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Abstract TP144: Preclinical Translation and Validation of C3a Receptor Antagonist in Thromboembolic Stroke
Stroke, 2019Co-Authors: Saif Ahmad, Rafay Chaudhary, Adam Kindelin, Chirayu D. Pandya, Nasrul Hoda, Andrew F. DucruetAbstract:Background: Activation of complement component C3 and expression of cerebro-endothelial C3a Receptor (C3aR) occur after stroke regardless of the dynamics of cerebral blood flow (CBF) changes. Moreo...
François G. Gervais - One of the best experts on this subject based on the ideXlab platform.
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the C3a Receptor antagonist sb 290157 has agonist activity
Immunology Letters, 2005Co-Authors: Marie-claude Mathieu, Nicole Sawyer, Gillian Greig, Martine Hamel, Stacia Kargman, Yves Ducharme, Cheuk K. Lau, Richard Friesen, Gary P Oneill, François G. GervaisAbstract:Abstract The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its Receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a β-lactamase assay in CHO-NFAT-bla-Gα16 cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
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The C3a Receptor antagonist SB 290157 has agonist activity.
Immunology letters, 2005Co-Authors: Marie-claude Mathieu, Nicole Sawyer, Gillian Greig, Martine Hamel, Stacia Kargman, Yves Ducharme, Cheuk K. Lau, Richard Friesen, Gary P. O'neill, François G. GervaisAbstract:The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its Receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
Andreas Klos - One of the best experts on this subject based on the ideXlab platform.
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The Complement C3a Receptor Is Critical in Defense against Chlamydia psittaci in Mouse Lung Infection and Required for Antibody and
2016Co-Authors: Optimal Cell T Response, Oliver Pabst, Andreas KlosAbstract:Background. The complement system protects against extracellular pathogens and links innate and adaptive immunity. In this study, we investigated the anaphylatoxin C3a Receptor (C3aR) in Chlamydia psittaci lung infection and elucidated C3a-dependent adaptive immune mechanisms. Methods. Survival, body weight, and clinical score were monitored in primary mouse infection and after serum transfer. Bacterial load, histology, cellular distribution, cytokines, antibodies, and lymphocytes were analyzed. Results. C3aR−/ − mice showed prolonged pneumonia with decreased survival, lower weight, and higher clinical score. Compared to wild-type mice bacterial clearance was impaired, and inflammatory parameters were increased. In lung-draining lymph nodes of C3aR−/ − mice the total number of B cells, CD4+ T cells, and Chlamydia-specific IFN-γ+ (CD4+ or CD8+) cells was reduced upon infection, and the mice were incapable of Chlamydia-specific im-munoglobulin M or immunoglobulin G production. Performed before infection, transfer of hyperimmune serum prolonged survival of C3aR−/−mice. Conclusions. C3a and its Receptor are critical for defense against C. psittaci in mouse lung infection. In this model, C3a acts via its Receptor as immune modulator. Enhancement of specific B and T cell responses upon infec-tion with an intracellular bacterium were identified as hitherto unknown features of C3a/C3aR. These new functions might be of general immunological importance
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the complement anaphylatoxin C3a Receptor C3ar contributes to the inflammatory response in dextran sulfate sodium dss induced colitis in mice
PLOS ONE, 2012Co-Authors: Elisabeth Wende, Rick A Wetsel, Robert Laudeley, Andre Bleich, Eva Bleich, Silke Glage, Andreas KlosAbstract:Inflammatory bowel diseases are a critical public health issue, and as treatment options remain limited, there is a need to unravel the underlying pathomechanisms in order to identify new therapeutic targets. Complement activation was found in patients suffering from inflammatory bowel disease, and the complement anaphylatoxin C5a and its Receptor C5aR have been implicated in disease pathogenesis in animal models of bowel inflammation. To further characterize complement-related pathomechanisms in inflammatory bowel disease, we have investigated the role of the anaphylatoxin C3a Receptor in acute dextran sulfate sodium-induced colitis in mice. For this, colitis was induced in C3a Receptor-deficient BALB/c and C57BL/6 mice, and disease severity was evaluated by clinical and histological examination, and by measuring the mRNA expression or protein levels of inflammatory mediators in the tissue. C3a Receptor deficiency was partially protective in BALB/c mice, which had significantly reduced weight loss, clinical and histological scores, colon shortening, and CXCL-1/KC mRNA, myeloperoxidase and interleukin-6 tissue levels compared to the corresponding wild type mice. In C57BL/6 mice the differences between wild type and C3a Receptor-deficient animals were much smaller and reached no significance. Our data demonstrate that the contribution of C3a Receptor to disease pathogenesis and severity of dextran sulfate sodium-induced colitis in mice depends on the genetic background. Further studies will be required to clarify whether targeting of C3a Receptor, possibly in combination with C5a Receptor, might be considered as a therapeutic strategy for inflammatory bowel disease.
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Phosphorylation of C3a Receptor at multiple sites mediates desensitization, β-arrestin-2 recruitment and inhibition of NF-κB activity in mast cells.
PloS one, 2012Co-Authors: Kshitij Gupta, Andreas Klos, Hariharan Subramanian, Hydar AliAbstract:Background Phosphorylation of G protein coupled Receptors (GPCRs) by G protein coupled Receptor kinases (GRKs) and the subsequent recruitment of β-arrestins are important for their desensitization. Using shRNA-mediated gene silencing strategy, we have recently shown that GRK2, GRK3 and β-arrestin-2 promote C3a Receptor (C3aR) desensitization in human mast cells. We also demonstrated that β-arrestin-2 provides an inhibitory signal for NF-κB activation. C3aR possesses ten potential phosphorylation sites within its carboxyl terminus but their role on desensitization, β-arrestin recruitment and NF-κB activation has not been determined. Methodology/Principal Findings We utilized a site directed mutagenesis approach in transfected HEK293 cells to determine the role of Receptor phosphorylation on β-arrestin-2 recruitment and RBL-2H3 cells for functional studies. We found that although Ala substitution of Ser475/479, Thr480/481 residues resulted in 58±3.8% decrease in agonist-induced C3aR phosphorylation there was no change in β-arrestin-2 binding or Receptor desensitization. By contrast, Ala substitution of Thr463, Ser465, Thr466 and Ser470 led to 40±1.3% decrease in agonist-induced Receptor phosphorylation but this was associated with 74±2.4% decreases in β-arrestin-2 binding, significantly reduced desensitization and enhanced NF-κB activation. Combined mutation of these Ser/Thr residues along with Ser459 (mutant MT7), resulted in complete loss of Receptor phosphorylation and β-arrestin-2 binding. RBL-2H3 cells expressing MT7 responded to C3a for greater Ca2+ mobilization, degranulation and NF-κB activation when compared to the wild-type Receptor. Interestingly, co-expression of MT7 with a constitutively active mutant of β-arrestin (R169E) inhibited C3a-induced degranulation by 28±2.4% and blocked NF-κB activation by 80±2.4%. Conclusion/Significance This study demonstrates that although C3a causes phosphorylation of its Receptor at multiple sites, Ser459, Thr463, Ser465, Thr466 and Ser470 participate in C3aR desensitization, β-arrestin-2 recruitment and inhibition of NF-κB activity. Furthermore, β-arrestin-2 inhibits C3a-induced NF-κB activation via Receptor desensitization-dependent and independent pathways.
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The transcription factors AP-1 and Ets are regulators of C3a Receptor expression.
The Journal of biological chemistry, 2005Co-Authors: Myriam Schaefer, Bettina Sohns, Claudia Rheinheimer, Stephanie Konrad, Jessica Thalmann, Kay Johswich, Andreas KlosAbstract:The anaphylatoxin C3a is a proinflammatory mediator generated during complement activation. The tight control of C3a Receptor (C3aR) expression is crucial for the regulation of anaphylatoxin-mediated effects. Key factors regulating constitutive expression of the C3aR in the mast cell line HMC-1 and Receptor induction by dibutyryl-cAMP in monomyeloblastic U937 cells were determined by functional characterization of the C3aR promoter. Nucleotides -18 to -285 upstream of the translational start site proved to be critical for promoter activity in HMC-1 cells. Binding sites for the transcription factors AP-1 and Ets could be located. Overexpressed c-Jun/c-Fos (AP-1) and Ets-1 led synergistically to increased promoter activity that was substantially reduced by site-directed mutagenesis of the corresponding elements within the C3aR promoter. In HMC-1 cells, Ets interacted directly with the predicted binding motif of the C3aR promoter as determined by electromobility shift assays. AP-1 binding to the C3aR promoter was augmented during C3aR induction in U937 cells. A retroviral gene transfer system was used to express a dominant negative mutant of Ets-1 in these cells. The resulting cells failed to up-regulate the C3aR after stimulation with dibutyryl-cAMP and showed decreased AP-1 binding, suggesting that Ets acts here indirectly. Thus, it was established that Ets and the AP-1 element mediates dibutyryl-cAMP induction of C3aR promoter activity, hence providing a mechanistic explanation of dibutyryl-cAMP-dependent up-regulation of C3aR expression. In conclusion, this study demonstrates an important role of AP-1 and a member of the Ets family in the transcriptional regulation of C3aR expression, a prerequisite for the ability of C3a to participate in immunomodulation and inflammation.
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Structure-function studies of the C3a-Receptor: C-terminal serine and threonine residues which influence Receptor internalization and signaling
European journal of immunology, 2003Co-Authors: B. Settmacher, Robert S. Ames, Jörg Köhl, Daniel Bock, Claudia Rheinheimer, Myriam Schaefer, Henning Hamacher, Alan Wise, Lesley Jenkinson, Andreas KlosAbstract:The anaphylatoxic peptide C3a is a pro-inflammatory mediator generated during complement activation, whose specific G protein coupled Receptor is expressed on granulocytes, monocytes, mast cells, activated lymphocytes, and in the nervous tissue. We have generated RBL-2H3 cell clones stably expressing mutants of the human C3a-Receptor (C3aR) with combined alanine (Ala) substitutions of ten C-terminal serine (Ser) or threonine (Thr) residues, which may represent putative phosphorylation sites to characterize their role in ligand-induced C3aR internalization and signaling. Ser475/479 and Thr480/481 as well as Ser449 seemed not to be involved in ligand-induced Receptor internalization. Either directly or by a conformational change they even "inhibit" C3aR internalization. In contrast, mutants with Ala substitutions at Ser465/470 and Thr463/466 were poorly internalized, and Thr463 seemed to be the most important C-terminal Thr or Ser residue directly effecting Receptor internalization. However, it is likely that other C3aR regions additionally participate in this negative feed-back mechanism since even mutants with multiple Ala substitutions still internalized to a limited degree. Interestingly, in a mutant with a single exchange of Ser449 to Ala, the signal transduction assessed by a Ca(2+) assay and [(35)S]GTP gamma S-binding on HEK cells transiently co-transfected with G-alpha 16 or G-alpha O, respectively, was severely impaired, indicating that this residue of C3aR is involved in G protein coupling.
Saif Ahmad - One of the best experts on this subject based on the ideXlab platform.
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abstract p732 genetic ablation of endothelial C3a Receptor confers cerebrovascular protection independent of the dynamics of reperfusion in stroke
Stroke, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Nasrul Hoda, Sara Bowen, Michael F Waters, Andrew F. DucruetAbstract:Background: Stroke enhances endothelial C3a Receptor (C3aREnd) expression and humoral levels of C3a which is further exacerbated by intravenous thrombolysis (IVT). Therefore, it is critical to inve...
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complement C3a Receptor mediated vascular dysfunction a complex interplay between aging and neurodegeneration
Journal of Clinical Investigation, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Kanchan Bhatia, Andrew F. DucruetAbstract:Vascular dysfunction resulting in compromised blood-brain barrier (BBB) integrity is evident in aging and disease. Although the complement C3a/C3a Receptor (C3a/C3aR) axis influences normal brain aging and disease progression, the mechanisms governing endothelial C3aR-mediated neurovascular inflammation and BBB permeability remain unexplored. In this issue of the JCI, Propson et al. investigated endothelial C3a/C3aR signaling in normal, aged, and neurodegenerative mouse models. Endothelial C3aR signaling modulated age-dependent increases in VCAM1, initiated peripheral lymphocyte infiltration, and enhanced microglial activity. Increased calcium release downstream of C3aR signaling disrupted the vascular endothelial cadherin (VE-cadherin) junctions, increased BBB permeability, and degraded vascular structure and function. Mice lacking C3aR (C3ar1-/-) and mice treated with a C3aR antagonist showed attenuated age-related microglial reactivity and neurodegeneration. These results confirm that complement-mediated signaling impacts vascular health and BBB function in normal aging and neurodegenerative disease, suggesting that complement inhibitors represent a therapeutic option for cerebral microvascular dysfunction.
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Abstract P772: Complement C3a Receptor Deletion is Neuroprotective in a Murine Model of Vascular Cognitive Impairment
Stroke, 2021Co-Authors: Saif Ahmad, Adam Kindelin, Kanchan Bhatia, Michael F Waters, Muhammed Nadeem, Laura Mahady, Alberto Fuentes, Gregory H Turner, Sadanand Fulzele, Nasrul HodaAbstract:Background: Chronic cerebral hypoperfusion (CCH) leads to vascular contributions to cognitive impairment and dementia (VCID). We and others have reported that either the genetic deficiency of complement C3a Receptor (C3aR) or its pharmacological inhibition in rodents protect against cerebral ischemia. Hypothesis: CCH augments VCID via overactivation of C3aR in brain. Methods: Male C3aR knockout (C3aR -/- ) and wild-type (C3aR +/+ ) mice (Age:12 weeks; N=8-10/gp) were subjected to either VCID with bilateral common carotid artery stenosis (BCAS) or sham surgery. At 4-mo post-BCAS, changes in cerebral blood flow (CBF), hippocampal atrophy (HA), white matter degeneration (WMD) and ventricular size were determined with laser speckle contrast analysis and magnetic resonance imaging. Behavioral outcomes were evaluated using Morris water maze (MWM) and novel object recognition (NOR). Histopathology with Luxol-Fast Blue (LFB) staining, and protein biochemistry with Western blotting were also performed. Results: BCAS resulted in reduced CBF, inducing HA, WMD and ventricle enlargement in both groups compared to their sham controls. These deleterious findings were attenuated in C3aR -/- compared to C3aR +/+ mice. Moreover, the C3aR -/- -BCAS group performed significantly better than C3aR +/+ -BCAS group in MWM and NOR tests; however, mice subjected to BCAS never outperformed their sham-groups. WMD demonstrated by LFB-staining and reduced expression of myelin basic protein and tight junction proteins (ZO-1 and Occludin) in mice subjected to BCAS was mitigated in C3aR -/- as compared to C3aR +/+ mice. C3aR +/+ -BCAS also showed significantly higher expression of C3a in plasma and C3aR in brain lysates compared to their sham-controls. Conclusion: CCH augments C3aR activation leading to poor outcomes in VCID. Therefore, future studies in cell-specific mutant mice are warranted to understand the pathological role of C3aR in VCID.
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Abstract P732: Genetic Ablation of Endothelial C3a-Receptor Confers Cerebrovascular Protection Independent of the Dynamics of Reperfusion in Stroke
Stroke, 2021Co-Authors: Adam Kindelin, Saif Ahmad, Nasrul Hoda, Sara Bowen, Michael F Waters, Andrew F. DucruetAbstract:Background: Stroke enhances endothelial C3a Receptor (C3aR End ) expression and humoral levels of C3a which is further exacerbated by intravenous thrombolysis (IVT). Therefore, it is critical to investigate the role of C3aR End in post-stroke neurovascular injury. Hypothesis: Genetic depletion of C3aR is vasculoprotective in stroke. Methods: Using a loxP - Cre approach (C3aR Flox/Flox xCdh5 Cre ), we generated mice conditionally deficient or sufficient in C3aR End (C3aR End-/- or C3aR End+/+ ), and subjected males (6±0.5-mo old) to thrombotic stroke (TS). Cerebral blood flow (CBF), behavioral outcomes, infarct volume, blood brain barrier (BBB) leakage, brain hemoglobin (Hb) content, brain tissue oxygen (PbtO 2 ) , neutrophil polarization ( Proinflammatory N1: Li6G + CD206 - vs. Antiinflammatory N2: Li6G + CD206 + ) and their brain infiltration were analyzed. P<0.05 was considered statistically significant. Results: TS resulted in similar degree of cerebral ischemia in both groups (N=10/gp); however, CBF, behavior, and infarct volume were significantly improved in C3aR End-/- vs. C3aR End+/+ mice at 72h post-TS. BBB-leakage and brain-Hb at 72h were less in C3aR End-/- vs. C3aR End+/+ mice but this did not meet significance (N=5/gp). Interestingly, C3a infusion 3h post-TS significantly enhanced BBB-leakage and brain-Hb in C3aR End+/+ but not in C3aR End-/- mice at 72h (N=5/gp), demonstrating that C3a in conjunction with C3aR End exacerbates neurovascular injury in TS. Moreover, late-IVT at 4h post-TS (2 mg/kgbwt; N=8/gp) significantly enhanced PbtO 2 in C3aR End-/- vs. C3aR End+/+ mice when assessed at 6h. Finally, C3aR deficiency significantly enhanced the N2/N1 ratio relative to the C3aR sufficient group at 24h post-TS (N=3/gp); thus inducing an anti-inflammatory effect and reduced neutrophil brain infiltration. Conclusion: C3aR End plays a critical role in stroke injury. Future studies targeting brain specific C3aR End are warranted.
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the role of complement C3a Receptor in stroke
Neuromolecular Medicine, 2019Co-Authors: Saif Ahmad, Adam Kindelin, Kanchan Bhatia, Andrew F. DucruetAbstract:The complement system is a key regulator of the innate immune response against diseased tissue that functions across multiple organ systems. Dysregulation of complement contributes to the pathogenesis of a number of neurological diseases including stroke. The C3a anaphylatoxin, via its cognate C3a Receptor (C3aR), mediates inflammation by promoting breakdown of the blood-brain barrier and the massive infiltration of leukocytes into ischemic brain in experimental stroke models. Studies utilizing complement deficient mice as well as pharmacologic C3aR antagonists have shown a reduction in tissue injury and mortality in murine stroke models. The development of tissue-specific C3aR knockout mice and more specific C3aR antagonists is warranted to facilitate our understanding of the role of the C3aR in brain ischemia with the ultimate goal of clinical translation of therapies targeting C3aR in stroke patients.
Marie-claude Mathieu - One of the best experts on this subject based on the ideXlab platform.
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the C3a Receptor antagonist sb 290157 has agonist activity
Immunology Letters, 2005Co-Authors: Marie-claude Mathieu, Nicole Sawyer, Gillian Greig, Martine Hamel, Stacia Kargman, Yves Ducharme, Cheuk K. Lau, Richard Friesen, Gary P Oneill, François G. GervaisAbstract:Abstract The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its Receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a β-lactamase assay in CHO-NFAT-bla-Gα16 cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.
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The C3a Receptor antagonist SB 290157 has agonist activity.
Immunology letters, 2005Co-Authors: Marie-claude Mathieu, Nicole Sawyer, Gillian Greig, Martine Hamel, Stacia Kargman, Yves Ducharme, Cheuk K. Lau, Richard Friesen, Gary P. O'neill, François G. GervaisAbstract:The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its Receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the current study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-Galpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists.