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Pesquisa : D12.776.124.486.274.024.270 [Categoria DeCS]
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  1 / 2339 MEDLINE  
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[PMID]:29220376
[Au] Autor:Hornum L; Hansen AJ; Tornehave D; Fjording MS; Colmenero P; Wätjen IF; Søe Nielsen NH; Bliddal H; Bartels EM
[Ad] Endereço:Novo Nordisk A/S, Måløv, Denmark.
[Ti] Título:C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid.
[So] Source:PLoS One;12(12):e0189017, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Complement activation correlates to rheumatoid arthritis disease activity, and increased amounts of the complement split product C5a is observed in synovial fluids from rheumatoid arthritis patients. Blockade of C5a or its receptor (C5aR) is efficacious in several arthritis models. The aim of this study was to investigate the role of C5a and C5aR in human rheumatoid arthritis and psoriatic arthritis-both with respect to expression and function. Synovial fluid, blood and synovial samples were obtained from rheumatoid arthritis, psoriatic arthritis and osteoarthritis patients as a less inflammatory arthritis type, and blood from healthy subjects. Cells infiltrating synovial tissue were analysed by immunohistochemistry and flow cytometry. SF and blood were analysed for biomarkers by flow cytometry or ELISA. The effect of a blocking anti-human C5aR mAb on leukocyte migration was determined using a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found in lymphoid aggregates in close contact with T cells. C5a levels were increased in both rheumatoid arthritis and psoriatic arthritis synovial fluid compared to osteoarthritis, and in blood from rheumatoid arthritis compared to healthy subjects. Neutrophil and monocyte migration to rheumatoid arthritis synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both diseases.
[Mh] Termos MeSH primário: Artrite Psoriásica/metabolismo
Artrite Reumatoide/metabolismo
Quimiotaxia de Leucócito
Complemento C5a/metabolismo
Leucócitos/patologia
Receptor da Anafilatoxina C5a/metabolismo
Líquido Sinovial/metabolismo
[Mh] Termos MeSH secundário: Ensaio de Imunoadsorção Enzimática
Citometria de Fluxo
Seres Humanos
Imuno-Histoquímica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189017


  2 / 2339 MEDLINE  
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[PMID]:29031586
[Au] Autor:Chen J; Li GQ; Zhang L; Tang M; Cao X; Xu GL; Wu YZ
[Ad] Endereço:Department of Immunology, Third Military Medical University, Chongqing 400038, PR China.
[Ti] Título:Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression.
[So] Source:Cancer Lett;412:30-36, 2018 Jan 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stageâ… to stage â…£), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression. Blockage of C5a/C5aR signaling with a C5aR antagonist reversed the C5a-induced inhibitory effect on p21/p-p21 expression. C5a administration to cells pre-treated with a PI3K inhibitor also prevented this inhibitory effect, suggesting the involvement of the PI3K/AKT signaling pathway in C5a/C5aR-mediated suppression of p21/p-p21 expression. In vivo C5aR antagonist treatment caused significant reduction in tumor growth in mice, accompanied by a remarkable elevation in p21/p-p21 expression and reduction in p-PI3K/AKT activation. These results indicate that the C5a/C5aR pathway promotes gastric cancer pathogenesis by suppressing p21/p-p21 expression via activation of PI3K/AKT signaling.
[Mh] Termos MeSH primário: Complemento C5a/fisiologia
Inibidor de Quinase Dependente de Ciclina p21/antagonistas & inibidores
Receptor da Anafilatoxina C5a/fisiologia
Transdução de Sinais/fisiologia
Neoplasias Gástricas/etiologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Inibidor de Quinase Dependente de Ciclina p21/fisiologia
Regulação para Baixo
Feminino
Seres Humanos
Masculino
Camundongos
Fosfatidilinositol 3-Quinases/fisiologia
Proteínas Proto-Oncogênicas c-akt/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5AR1 protein, human); 0 (CDKN1A protein, human); 0 (Cyclin-Dependent Kinase Inhibitor p21); 0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


  3 / 2339 MEDLINE  
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[PMID]:28931049
[Au] Autor:Wiese AV; Ender F; Quell KM; Antoniou K; Vollbrandt T; König P; Köhl J; Laumonnier Y
[Ad] Endereço:Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
[Ti] Título:The C5a/C5aR1 axis controls the development of experimental allergic asthma independent of LysM-expressing pulmonary immune cells.
[So] Source:PLoS One;12(9):e0184956, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. Here, we determined the role of C5aR1 signaling in neutrophils, moDCs and macrophages for the pulmonary recruitment of such cells and the importance of C5aR1-mediated activation of LysM-expressing cells for the development of allergic asthma. We used LysM-C5aR1 KO mice with a specific deletion of C5aR1 in LysMCre-expressing cells and confirmed the specific deletion of C5aR1 in neutrophils, macrophages and moDCs in the airways and/or the lung tissue. We found that alveolar macrophage numbers were significantly increased in LysM-C5aR1 KO mice. Induction of ovalbumin (OVA)-driven experimental allergic asthma in GFP-C5aR1fl/fl and LysM-C5aR1 KO mice resulted in strong but similar airway resistance, mucus production and Th2/Th17 cytokine production. In contrast, the number of airway but not of pulmonary neutrophils was lower in LysM-C5aR1 KO as compared with GFP-C5aR1fl/fl mice. The recruitment of macrophages, cDCs, moDCs, T cells and type 2 innate lymphoid cells was not altered in LysM-C5aR1 KO mice. Our findings demonstrate that C5aR1 is critical for steady state control of alveolar macrophage numbers and the transition of neutrophils from the lung into the airways in OVA-driven allergic asthma. However, C5aR1 activation of LysM-expressing cells plays a surprisingly minor role in the recruitment and activation of such cells and the development of the allergic phenotype in OVA-driven experimental allergic asthma.
[Mh] Termos MeSH primário: Asma/patologia
Complemento C5a/metabolismo
Pulmão/imunologia
Muramidase/fisiologia
Receptor da Anafilatoxina C5a/fisiologia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Asma/induzido quimicamente
Asma/imunologia
Células Cultivadas
Células Dendríticas/imunologia
Células Dendríticas/metabolismo
Eosinófilos/imunologia
Eosinófilos/metabolismo
Pulmão/metabolismo
Pulmão/patologia
Macrófagos/imunologia
Macrófagos/metabolismo
Camundongos
Camundongos Knockout
Neutrófilos/imunologia
Neutrófilos/metabolismo
Ovalbumina/toxicidade
Linfócitos T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar1 protein, mouse); 0 (Receptor, Anaphylatoxin C5a); 80295-54-1 (Complement C5a); 9006-59-1 (Ovalbumin); EC 3.2.1.17 (Muramidase); EC 3.2.1.17 (lysozyme M, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184956


  4 / 2339 MEDLINE  
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[PMID]:28671713
[Au] Autor:Denk S; Taylor RP; Wiegner R; Cook EM; Lindorfer MA; Pfeiffer K; Paschke S; Eiseler T; Weiss M; Barth E; Lambris JD; Kalbitz M; Martin T; Barth H; Messerer DAC; Gebhard F; Huber-Lang MS
[Ad] Endereço:Institute of Clinical and Experimental Trauma-Immunology, University Hospital Ulm, Ulm, Germany.
[Ti] Título:Complement C5a-Induced Changes in Neutrophil Morphology During Inflammation.
[So] Source:Scand J Immunol;86(3):143-155, 2017 Sep.
[Is] ISSN:1365-3083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement and neutrophil defence systems, as major components of innate immunity, are activated during inflammation and infection. For neutrophil migration to the inflamed region, we hypothesized that the complement activation product C5a induces significant changes in cellular morphology before chemotaxis. Exposure of human neutrophils to C5a dose- and time-dependently resulted in a rapid C5a receptor-1 (C5aR1)-dependent shape change, indicated by enhanced flow cytometric forward-scatter area values. Similar changes were observed after incubation with zymosan-activated serum and in blood neutrophils during murine sepsis, but not in mice lacking the C5aR1. In human neutrophils, Amnis high-resolution digital imaging revealed a C5a-induced decrease in circularity and increase in the cellular length/width ratio. Biomechanically, microfluidic optical stretching experiments indicated significantly increased neutrophil deformability early after C5a stimulation. The C5a-induced shape changes were inhibited by pharmacological blockade of either the Cl-/HCO3--exchanger or the Cl -channel. Furthermore, actin polymerization assays revealed that C5a exposure resulted in a significant polarization of the neutrophils. The functional polarization process triggered by ATP-P2X/Y-purinoceptor interaction was also involved in the C5a-induced shape changes, because pretreatment with suramin blocked not only the shape changes but also the subsequent C5a-dependent chemotactic activity. In conclusion, the data suggest that the anaphylatoxin C5a regulates basic neutrophil cell processes by increasing the membrane elasticity and cell size as a consequence of actin-cytoskeleton polymerization and reorganization, transforming the neutrophil into a migratory cell able to invade the inflammatory site and subsequently clear pathogens and molecular debris.
[Mh] Termos MeSH primário: Citoesqueleto de Actina/imunologia
Forma Celular/imunologia
Complemento C5a/metabolismo
Inflamação/imunologia
Neutrófilos/imunologia
[Mh] Termos MeSH secundário: Actinas/metabolismo
Trifosfato de Adenosina/metabolismo
Células Cultivadas
Quimiotaxia
Antiportadores de Cloreto-Bicarbonato/metabolismo
Complemento C5a/imunologia
Seres Humanos
Ativação de Neutrófilo
Neutrófilos/patologia
Receptor da Anafilatoxina C5a/metabolismo
Receptores Purinérgicos P2X/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (C5AR1 protein, human); 0 (Chloride-Bicarbonate Antiporters); 0 (Receptor, Anaphylatoxin C5a); 0 (Receptors, Purinergic P2X); 80295-54-1 (Complement C5a); 8L70Q75FXE (Adenosine Triphosphate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1111/sji.12580


  5 / 2339 MEDLINE  
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[PMID]:28652401
[Au] Autor:Bettoni S; Galbusera M; Gastoldi S; Donadelli R; Tentori C; Spartà G; Bresin E; Mele C; Alberti M; Tortajada A; Yebenes H; Remuzzi G; Noris M
[Ad] Endereço:IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," 24020 Ranica Bergamo, Italy.
[Ti] Título:Interaction between Multimeric von Willebrand Factor and Complement: A Fresh Look to the Pathophysiology of Microvascular Thrombosis.
[So] Source:J Immunol;199(3):1021-1040, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:von Willebrand factor (VWF), a multimeric protein with a central role in hemostasis, has been shown to interact with complement components. However, results are contrasting and inconclusive. By studying 20 patients with congenital thrombotic thrombocytopenic purpura (cTTP) who cannot cleave VWF multimers because of genetic deficiency, we investigated the mechanism through which VWF modulates complement and its pathophysiological implications for human diseases. Using assays of ex vivo serum-induced C3 and C5b-9 deposits on endothelial cells, we documented that in cTTP, complement is activated via the alternative pathway (AP) on the cell surface. This abnormality was corrected by restoring ADAMTS13 activity in cTTP serum, which prevented VWF multimer accumulation on endothelial cells, or by an anti-VWF Ab. In mechanistic studies we found that VWF interacts with C3b through its three type A domains and initiates AP activation, although assembly of active C5 convertase and formation of the terminal complement products C5a and C5b-9 occur only on the VWF-A2 domain. Finally, we documented that in the condition of ADAMTS13 deficiency, VWF-mediated formation of terminal complement products, particularly C5a, alters the endothelial antithrombogenic properties and induces microvascular thrombosis in a perfusion system. Altogether, the results demonstrated that VWF provides a platform for the activation of the AP of complement, which profoundly alters the phenotype of microvascular endothelial cells. These findings link hemostasis-thrombosis with the AP of complement and open new therapeutic perspectives in cTTP and in general in thrombotic and inflammatory disorders associated with endothelium perturbation, VWF release, and complement activation.
[Mh] Termos MeSH primário: Complemento C3b/metabolismo
Via Alternativa do Complemento
Células Endoteliais/imunologia
Microvasos/patologia
Trombose/fisiopatologia
Fator de von Willebrand/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS13/sangue
Proteína ADAMTS13/deficiência
Proteína ADAMTS13/imunologia
Proteína ADAMTS13/metabolismo
Adolescente
Adulto
Criança
Pré-Escolar
Convertases de Complemento C3-C5/metabolismo
Complemento C3b/imunologia
Complemento C5a/imunologia
Complemento C5a/metabolismo
Complexo de Ataque à Membrana do Sistema Complemento/imunologia
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Feminino
Seres Humanos
Recém-Nascido
Masculino
Microvasos/imunologia
Púrpura Trombocitopênica Trombótica/congênito
Púrpura Trombocitopênica Trombótica/imunologia
Púrpura Trombocitopênica Trombótica/fisiopatologia
Trombose/imunologia
Adulto Jovem
Fator de von Willebrand/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement Membrane Attack Complex); 0 (von Willebrand Factor); 80295-43-8 (Complement C3b); 80295-54-1 (Complement C5a); EC 3.4.21.- (Complement C3-C5 Convertases); EC 3.4.24.87 (ADAMTS13 Protein); EC 3.4.24.87 (ADAMTS13 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601121


  6 / 2339 MEDLINE  
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[PMID]:28640789
[Au] Autor:Valenzuela NM; Thomas KA; Mulder A; Parry GC; Panicker S; Reed EF
[Ad] Endereço:1 UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA.2 Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.3 True North Therapeutics Inc., South San Francisco, CA.
[Ti] Título:Complement-Mediated Enhancement of Monocyte Adhesion to Endothelial Cells by HLA Antibodies, and Blockade by a Specific Inhibitor of the Classical Complement Cascade, TNT003.
[So] Source:Transplantation;101(7):1559-1572, 2017 Jul.
[Is] ISSN:1534-6080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Antibody-mediated rejection (AMR) of most solid organs is characterized by evidence of complement activation and/or intragraft macrophages (C4d + and CD68+ biopsies). We previously demonstrated that crosslinking of HLA I by antibodies triggered endothelial activation and monocyte adhesion. We hypothesized that activation of the classical complement pathway at the endothelial cell surface by HLA antibodies would enhance monocyte adhesion through soluble split product generation, in parallel with direct endothelial activation downstream of HLA signaling. METHODS: Primary human aortic endothelial cells (HAEC) were stimulated with HLA class I antibodies in the presence of intact human serum complement. C3a and C5a generation, endothelial P-selectin expression, and adhesion of human primary and immortalized monocytes (Mono Mac 6) were measured. Alternatively, HAEC or monocytes were directly stimulated with purified C3a or C5a. Classical complement activation was inhibited by pretreatment of complement with an anti-C1s antibody (TNT003). RESULTS: Treatment of HAEC with HLA antibody and human complement increased the formation of C3a and C5a. Monocyte recruitment by human HLA antibodies was enhanced in the presence of intact human serum complement or purified C3a or C5a. Specific inhibition of the classical complement pathway using TNT003 or C1q-depleted serum significantly reduced adhesion of monocytes in the presence of human complement. CONCLUSIONS: Despite persistent endothelial viability in the presence of HLA antibodies and complement, upstream complement anaphylatoxin production exacerbates endothelial exocytosis and leukocyte recruitment. Upstream inhibition of classical complement may be therapeutic to dampen mononuclear cell recruitment and endothelial activation characteristic of microvascular inflammation during AMR.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Adesão Celular/efeitos dos fármacos
Inativadores do Complemento/farmacologia
Via Clássica do Complemento/efeitos dos fármacos
Células Endoteliais/efeitos dos fármacos
Antígenos HLA-A/imunologia
Imunossupressores/farmacologia
Monócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Células Cultivadas
Técnicas de Cocultura
Complemento C3a/farmacologia
Complemento C5a/farmacologia
Relação Dose-Resposta a Droga
Células Endoteliais/imunologia
Células Endoteliais/metabolismo
Exocitose/efeitos dos fármacos
Antígenos HLA-A/metabolismo
Seres Humanos
Antígeno de Macrófago 1/imunologia
Antígeno de Macrófago 1/metabolismo
Monócitos/imunologia
Monócitos/metabolismo
Selectina-P/imunologia
Selectina-P/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Complement Inactivating Agents); 0 (HLA-A Antigens); 0 (Immunosuppressive Agents); 0 (Macrophage-1 Antigen); 0 (P-Selectin); 0 (SELP protein, human); 0 (TNT003); 80295-42-7 (Complement C3a); 80295-54-1 (Complement C5a)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1097/TP.0000000000001486


  7 / 2339 MEDLINE  
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[PMID]:28614388
[Au] Autor:Bergdolt S; Kovtun A; Hägele Y; Liedert A; Schinke T; Amling M; Huber-Lang M; Ignatius A
[Ad] Endereço:Institute of Orthopedic Research and Biomechanics, University of Ulm, Ulm, Germany.
[Ti] Título:Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing.
[So] Source:PLoS One;12(6):e0179512, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.
[Mh] Termos MeSH primário: Consolidação da Fratura/genética
Regulação da Expressão Gênica
Osteoblastos/metabolismo
Receptor da Anafilatoxina C5a/genética
[Mh] Termos MeSH secundário: Animais
Western Blotting
Líquido da Lavagem Broncoalveolar/química
Células Cultivadas
Colágeno Tipo I/genética
Colágeno Tipo I/metabolismo
Complemento C5a/metabolismo
Fêmur/diagnóstico por imagem
Fêmur/metabolismo
Fêmur/cirurgia
Interleucina-6/genética
Interleucina-6/metabolismo
Camundongos
Osteoblastos/citologia
Osteogênese/genética
Osteoprotegerina/genética
Osteoprotegerina/metabolismo
Fosforilação
Ligante RANK/genética
Ligante RANK/metabolismo
Receptor da Anafilatoxina C5a/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transdução de Sinais/genética
Regulação para Cima
Microtomografia por Raio-X/métodos
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (C5ar1 protein, mouse); 0 (Collagen Type I); 0 (Interleukin-6); 0 (Osteoprotegerin); 0 (RANK Ligand); 0 (Receptor, Anaphylatoxin C5a); 0 (TNFSF11 protein, human); 0 (collagen type I, alpha 1 chain); 80295-54-1 (Complement C5a); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0179512


  8 / 2339 MEDLINE  
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[PMID]:28610663
[Au] Autor:Nilsson PH; Thomas AM; Bergseth G; Gustavsen A; Volokhina EB; van den Heuvel LP; Barratt-Due A; Mollnes TE
[Ad] Endereço:Department of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, University of Oslo, Oslo, Norway; Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
[Ti] Título:Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses.
[So] Source:Mol Immunol;89:111-114, 2017 Sep.
[Is] ISSN:1872-9142
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Ativação do Complemento/efeitos dos fármacos
Complemento C5/imunologia
Complemento C5a/imunologia
Complemento C5b/imunologia
[Mh] Termos MeSH secundário: Anticorpos Monoclonais Humanizados/metabolismo
Síndrome Hemolítico-Urêmica Atípica/sangue
Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico
Síndrome Hemolítico-Urêmica Atípica/imunologia
Cromatografia em Gel
Ativação do Complemento/imunologia
Complemento C5/metabolismo
Complemento C5a/metabolismo
Complemento C5b/metabolismo
Inativadores do Complemento/metabolismo
Inativadores do Complemento/uso terapêutico
Ensaio de Imunoadsorção Enzimática
Epitopos/imunologia
Epitopos/metabolismo
Hemoglobinúria Paroxística/sangue
Hemoglobinúria Paroxística/tratamento farmacológico
Hemoglobinúria Paroxística/imunologia
Seres Humanos
Concentração de Íons de Hidrogênio
Imunoglobulina G/sangue
Imunoglobulina G/imunologia
Avaliação de Resultados (Cuidados de Saúde)
Ligação Proteica/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Complement C5); 0 (Complement Inactivating Agents); 0 (Epitopes); 0 (Immunoglobulin G); 80295-54-1 (Complement C5a); 80295-55-2 (Complement C5b); A3ULP0F556 (eculizumab)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE


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[PMID]:28606989
[Au] Autor:Lood C; Arve S; Ledbetter J; Elkon KB
[Ad] Endereço:Department of Medicine, Division of Rheumatology, University of Washington, Seattle, WA 98109 KElkon@medicine.washington.edu Loodc@medicine.washington.edu.
[Ti] Título:TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA.
[So] Source:J Exp Med;214(7):2103-2119, 2017 Jul 03.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neutrophils play a crucial role in host defense. However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid-containing immune complexes (IC) drive inflammation. The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known. We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis. TLR7/8-activated neutrophils promoted cleavage of FcgRIIA on plasmacytoid dendritic cells and monocytes, resulting in impaired overall clearance of ICs and increased complement C5a generation. Importantly, ex vivo derived activated neutrophils from SLE patients demonstrated a similar cleavage of FcgRIIA that was correlated with markers of disease activity, as well as complement activation. Therapeutic approaches aimed at blocking TLR7/8 activation would be predicted to increase phagocytosis of circulating ICs, while disarming their inflammatory potential.
[Mh] Termos MeSH primário: Complexo Antígeno-Anticorpo/imunologia
Neutrófilos/imunologia
Fagocitose/imunologia
Receptores de IgG/imunologia
Receptor 7 Toll-Like/imunologia
Receptor 8 Toll-Like/imunologia
[Mh] Termos MeSH secundário: Western Blotting
Células Cultivadas
Ativação do Complemento/imunologia
Complemento C5a/imunologia
Complemento C5a/metabolismo
Células Dendríticas/imunologia
Células Dendríticas/metabolismo
Armadilhas Extracelulares/imunologia
Armadilhas Extracelulares/metabolismo
Citometria de Fluxo
Seres Humanos
Lúpus Eritematoso Sistêmico/imunologia
Lúpus Eritematoso Sistêmico/metabolismo
Monócitos/imunologia
Monócitos/metabolismo
Neutrófilos/metabolismo
Receptores de IgG/metabolismo
Receptor 7 Toll-Like/metabolismo
Receptor 8 Toll-Like/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigen-Antibody Complex); 0 (FCGR2A protein, human); 0 (Receptors, IgG); 0 (Toll-Like Receptor 7); 0 (Toll-Like Receptor 8); 80295-54-1 (Complement C5a)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20161512


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[PMID]:28579778
[Au] Autor:Wolf-Grosse S; Rokstad AM; Ali S; Lambris JD; Mollnes TE; Nilsen AM; Stenvik J
[Ad] Endereço:Department of Cancer Research and Molecular Medicine.
[Ti] Título:Iron oxide nanoparticles induce cytokine secretion in a complement-dependent manner in a human whole blood model.
[So] Source:Int J Nanomedicine;12:3927-3940, 2017.
[Is] ISSN:1178-2013
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Iron oxide nanoparticles (IONPs) are promising nanomaterials for biomedical applications. However, their inflammatory potential has not been fully established. Here, we used a lepirudin anti-coagulated human whole blood model to evaluate the potential of 10 nm IONPs to activate the complement system and induce cytokine production. Reactive oxygen species and cell death were also assessed. The IONPs activated complement, as measured by C3a, C5a and sC5b-9, and induced the production of pro-inflammatory cytokines in a particle-dose dependent manner, with the strongest response at 10 µg/mL IONPs. Complement inhibitors at C3 (compstatin analog Cp40) and C5 (eculizumab) levels completely inhibited complement activation and secretion of inflammatory mediators induced by the IONPs. Additionally, blockade of complement receptors C3aR and C5aR1 significantly reduced the levels of various cytokines, indicating that the particle-induced secretion of inflammatory mediators is mainly C5a and C3a mediated. The IONPs did not induce cell death or reactive oxygen species, which further suggests that complement activation alone was responsible for most of the particle-induced cytokines. These data suggest that the lepirudin anti-coagulated human whole blood model is a valuable ex vivo system to study the inflammatory potential of IONPs. We conclude that IONPs induce complement-mediated cytokine secretion in human whole blood.
[Mh] Termos MeSH primário: Ativação do Complemento
Citocinas/sangue
Compostos Férricos/química
Nanopartículas Metálicas/química
[Mh] Termos MeSH secundário: Anti-Inflamatórios/farmacologia
Anticoagulantes/farmacologia
Sobrevivência Celular
Complemento C3a/metabolismo
Complemento C5a/metabolismo
Complemento C5b/metabolismo
Inativadores do Complemento/farmacologia
Hirudinas/farmacologia
Seres Humanos
Tamanho da Partícula
Espécies Reativas de Oxigênio/sangue
Receptores de Complemento/sangue
Proteínas Recombinantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Anticoagulants); 0 (Complement Inactivating Agents); 0 (Cytokines); 0 (Ferric Compounds); 0 (Hirudins); 0 (Reactive Oxygen Species); 0 (Receptors, Complement); 0 (Recombinant Proteins); 1K09F3G675 (ferric oxide); 80295-42-7 (Complement C3a); 80295-54-1 (Complement C5a); 80295-55-2 (Complement C5b); Y43GF64R34 (lepirudin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE
[do] DOI:10.2147/IJN.S136453



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