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[PMID]:28867487
[Au] Autor:Rotty JD; Brighton HE; Craig SL; Asokan SB; Cheng N; Ting JP; Bear JE
[Ad] Endereço:UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
[Ti] Título:Arp2/3 Complex Is Required for Macrophage Integrin Functions but Is Dispensable for FcR Phagocytosis and In Vivo Motility.
[So] Source:Dev Cell;42(5):498-513.e6, 2017 Sep 11.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Arp2/3 complex nucleates branched actin, forming networks involved in lamellipodial protrusion, phagocytosis, and cell adhesion. We derived primary bone marrow macrophages lacking Arp2/3 complex (Arpc2 ) and directly tested its role in macrophage functions. Despite protrusion and actin assembly defects, Arpc2 macrophages competently phagocytose via FcR and chemotax toward CSF and CX3CL1. However, CR3 phagocytosis and fibronectin haptotaxis, both integrin-dependent processes, are disrupted. Integrin-responsive actin assembly and αM/ß2 integrin localization are compromised in Arpc2 cells. Using an in vivo system to observe endogenous monocytes migrating toward full-thickness ear wounds we found that Arpc2 monocytes maintain cell speeds and directionality similar to control. Our work reveals that the Arp2/3 complex is not a general requirement for phagocytosis or chemotaxis but is a critical driver of integrin-dependent processes. We demonstrate further that cells lacking Arp2/3 complex function in vivo remain capable of executing important physiological responses that require rapid directional motility.
[Mh] Termos MeSH primário: Complexo 2-3 de Proteínas Relacionadas à Actina/metabolismo
Movimento Celular
Integrinas/metabolismo
Macrófagos/citologia
Macrófagos/metabolismo
Fagocitose
Receptores Fc/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Movimento Celular/efeitos dos fármacos
Forma Celular/efeitos dos fármacos
Quimiocina CX3CL1/farmacologia
Quimiotaxia/efeitos dos fármacos
Fatores Estimuladores de Colônias/farmacologia
Feminino
Fibronectinas/farmacologia
Ligantes
Antígeno de Macrófago 1/metabolismo
Macrófagos/efeitos dos fármacos
Macrófagos/ultraestrutura
Masculino
Camundongos Endogâmicos C57BL
Cadeias Pesadas de Miosina/metabolismo
Fagocitose/efeitos dos fármacos
Fenótipo
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actin-Related Protein 2-3 Complex); 0 (Actins); 0 (Chemokine CX3CL1); 0 (Colony-Stimulating Factors); 0 (Fibronectins); 0 (Integrins); 0 (Ligands); 0 (Macrophage-1 Antigen); 0 (Receptors, Fc); 0 (Receptors, G-Protein-Coupled); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170905
[St] Status:MEDLINE


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[PMID]:28714582
[Au] Autor:Kragstrup TW; Juul-Madsen K; Christiansen SH; Zhang X; Krog J; Vorup-Jensen T; Kjaergaard AG
[Ad] Endereço:Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark.
[Ti] Título:Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis.
[So] Source:Clin Exp Immunol;190(2):258-267, 2017 Nov.
[Is] ISSN:1365-2249
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360-617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis.
[Mh] Termos MeSH primário: Antígenos CD18/sangue
Sepse/imunologia
Choque Séptico/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Biomarcadores/sangue
Adesão Celular
Feminino
Seres Humanos
Unidades de Terapia Intensiva
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/imunologia
Lipopolissacarídeos/imunologia
Antígeno-1 Associado à Função Linfocitária/metabolismo
Antígeno de Macrófago 1/metabolismo
Masculino
Meia-Idade
Sepse/fisiopatologia
Choque Séptico/fisiopatologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (CD18 Antigens); 0 (Lipopolysaccharides); 0 (Lymphocyte Function-Associated Antigen-1); 0 (Macrophage-1 Antigen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1111/cei.13016


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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


  4 / 3494 MEDLINE  
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[PMID]:28615221
[Au] Autor:Pick R; Begandt D; Stocker TJ; Salvermoser M; Thome S; Böttcher RT; Montanez E; Harrison U; Forné I; Khandoga AG; Coletti R; Weckbach LT; Brechtefeld D; Haas R; Imhof A; Massberg S; Sperandio M; Walzog B
[Ad] Endereço:Department of Cardiovascular Physiology and Pathophysiology, Walter Brendel Center of Experimental Medicine, Biomedical Center, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
[Ti] Título:Coronin 1A, a novel player in integrin biology, controls neutrophil trafficking in innate immunity.
[So] Source:Blood;130(7):847-858, 2017 Aug 17.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Trafficking of polymorphonuclear neutrophils (PMNs) during inflammation critically depends on the ß integrins lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) and macrophage-1 antigen (CD11b/CD18). Here, we identify coronin 1A (Coro1A) as a novel regulator of ß integrins that interacts with the cytoplasmic tail of CD18 and is crucial for induction of PMN adhesion and postadhesion events, including adhesion strengthening, spreading, and migration under flow conditions. Transition of PMN rolling to firm adhesion critically depends on Coro1A by regulating the accumulation of high-affinity LFA-1 in focal zones of adherent cells. Defective integrin affinity regulation in the genetic absence of impairs leukocyte adhesion and extravasation in inflamed cremaster muscle venules in comparison with control animals. In a mouse infection model, PMN infiltration into the gastric mucosa is dramatically reduced in mice, resulting in an attenuated gastric inflammation. Thus, Coro1A represents an important novel player in integrin biology, with key functions in PMN trafficking during innate immunity.
[Mh] Termos MeSH primário: 4-Butirolactona/análogos & derivados
Antígenos CD18/metabolismo
Movimento Celular
Imunidade Inata
Neutrófilos/citologia
Neutrófilos/metabolismo
[Mh] Termos MeSH secundário: 4-Butirolactona/metabolismo
Actinas/metabolismo
Animais
Sinalização do Cálcio
Adesão Celular
Gastrite/imunologia
Gastrite/microbiologia
Gastrite/patologia
Helicobacter pylori/fisiologia
Antígeno-1 Associado à Função Linfocitária/metabolismo
Antígeno de Macrófago 1/metabolismo
Camundongos Endogâmicos C57BL
Receptores Acoplados a Proteínas-G/metabolismo
Reologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (CD18 Antigens); 0 (Lymphocyte Function-Associated Antigen-1); 0 (Macrophage-1 Antigen); 0 (Receptors, G-Protein-Coupled); 0 (coronin); OL659KIY4X (4-Butyrolactone)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2016-11-749622


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[PMID]:28424516
[Au] Autor:Chen J; Zhong MC; Guo H; Davidson D; Mishel S; Lu Y; Rhee I; Pérez-Quintero LA; Zhang S; Cruz-Munoz ME; Wu N; Vinh DC; Sinha M; Calderon V; Lowell CA; Danska JS; Veillette A
[Ad] Endereço:Laboratory of Molecular Oncology, Institut de recherches cliniques de Montréal (IRCM), Montréal, Québec H2W 1R7, Canada.
[Ti] Título:SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin.
[So] Source:Nature;544(7651):493-497, 2017 04 27.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cancer cells elude anti-tumour immunity through multiple mechanisms, including upregulated expression of ligands for inhibitory immune checkpoint receptors. Phagocytosis by macrophages plays a critical role in cancer control. Therapeutic blockade of signal regulatory protein (SIRP)-α, an inhibitory receptor on macrophages, or of its ligand CD47 expressed on tumour cells, improves tumour cell elimination in vitro and in vivo, suggesting that blockade of the SIRPα-CD47 checkpoint could be useful in treating human cancer. However, the pro-phagocytic receptor(s) responsible for tumour cell phagocytosis is(are) largely unknown. Here we find that macrophages are much more efficient at phagocytosis of haematopoietic tumour cells, compared with non-haematopoietic tumour cells, in response to SIRPα-CD47 blockade. Using a mouse lacking the signalling lymphocytic activation molecule (SLAM) family of homotypic haematopoietic cell-specific receptors, we determined that phagocytosis of haematopoietic tumour cells during SIRPα-CD47 blockade was strictly dependent on SLAM family receptors in vitro and in vivo. In both mouse and human cells, this function required a single SLAM family member, SLAMF7 (also known as CRACC, CS1, CD319), expressed on macrophages and tumour cell targets. In contrast to most SLAM receptor functions, SLAMF7-mediated phagocytosis was independent of signalling lymphocyte activation molecule-associated protein (SAP) adaptors. Instead, it depended on the ability of SLAMF7 to interact with integrin Mac-1 (refs 18, 19, 20) and utilize signals involving immunoreceptor tyrosine-based activation motifs. These findings elucidate the mechanism by which macrophages engulf and destroy haematopoietic tumour cells. They also reveal a novel SAP adaptor-independent function for a SLAM receptor. Lastly, they suggest that patients with tumours expressing SLAMF7 are more likely to respond to SIRPα-CD47 blockade therapy.
[Mh] Termos MeSH primário: Neoplasias Hematológicas/imunologia
Neoplasias Hematológicas/patologia
Antígeno de Macrófago 1/metabolismo
Macrófagos/imunologia
Fagocitose/imunologia
Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
[Mh] Termos MeSH secundário: Actinas/metabolismo
Animais
Antígenos de Diferenciação/imunologia
Antígenos de Diferenciação/metabolismo
Antígeno CD47/imunologia
Antígeno CD47/metabolismo
Feminino
Neoplasias Hematológicas/tratamento farmacológico
Seres Humanos
Macrófagos/citologia
Macrófagos/metabolismo
Masculino
Camundongos
Camundongos Knockout
Receptores Imunológicos/antagonistas & inibidores
Receptores Imunológicos/imunologia
Receptores Imunológicos/metabolismo
Família de Moléculas de Sinalização da Ativação Linfocitária/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Actins); 0 (Antigens, Differentiation); 0 (CD47 Antigen); 0 (CD47 protein, human); 0 (Macrophage-1 Antigen); 0 (Receptors, Immunologic); 0 (SIRPA protein, human); 0 (SLAMF7 protein, human); 0 (Signaling Lymphocytic Activation Molecule Family); 0 (Slamf7 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1038/nature22076


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[PMID]:28408624
[Au] Autor:Healy LD; Puy C; Fernández JA; Mitrugno A; Keshari RS; Taku NA; Chu TT; Xu X; Gruber A; Lupu F; Griffin JH; McCarty OJT
[Ad] Endereço:From the Departments of Cell, Developmental & Cancer Biology and healyl@ohsu.edu.
[Ti] Título:Activated protein C inhibits neutrophil extracellular trap formation and activation .
[So] Source:J Biol Chem;292(21):8616-8629, 2017 May 26.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Activated protein C (APC) is a multifunctional serine protease with anticoagulant, cytoprotective, and anti-inflammatory activities. In addition to the cytoprotective effects of APC on endothelial cells, podocytes, and neurons, APC cleaves and detoxifies extracellular histones, a major component of neutrophil extracellular traps (NETs). NETs promote pathogen clearance but also can lead to thrombosis; the pathways that negatively regulate NETosis are largely unknown. Thus, we studied whether APC is capable of directly inhibiting NETosis via receptor-mediated cell signaling mechanisms. Here, by quantifying extracellular DNA or myeloperoxidase, we demonstrate that APC binds human leukocytes and prevents activated platelet supernatant or phorbol 12-myristate 13-acetate (PMA) from inducing NETosis. Of note, APC proteolytic activity was required for inhibiting NETosis. Moreover, antibodies against the neutrophil receptors endothelial protein C receptor (EPCR), protease-activated receptor 3 (PAR3), and macrophage-1 antigen (Mac-1) blocked APC inhibition of NETosis. Select mutations in the Gla and protease domains of recombinant APC caused a loss of NETosis. Interestingly, pretreatment of neutrophils with APC prior to induction of NETosis inhibited platelet adhesion to NETs. Lastly, in a nonhuman primate model of -induced sepsis, pretreatment of animals with APC abrogated release of myeloperoxidase from neutrophils, a marker of neutrophil activation. These findings suggest that the anti-inflammatory function of APC at therapeutic concentrations may include the inhibition of NETosis in an EPCR-, PAR3-, and Mac-1-dependent manner, providing additional mechanistic insight into the diverse functions of neutrophils and APC in disease states including sepsis.
[Mh] Termos MeSH primário: Armadilhas Extracelulares/imunologia
Ativação de Neutrófilo/imunologia
Neutrófilos/imunologia
Proteína C/imunologia
[Mh] Termos MeSH secundário: Animais
Antígenos CD/imunologia
Antígenos CD/metabolismo
Modelos Animais de Doenças
Receptor de Proteína C Endotelial
Escherichia coli
Infecções por Escherichia coli/sangue
Infecções por Escherichia coli/imunologia
Armadilhas Extracelulares/metabolismo
Feminino
Seres Humanos
Antígeno de Macrófago 1/imunologia
Antígeno de Macrófago 1/metabolismo
Masculino
Ativação de Neutrófilo/efeitos dos fármacos
Neutrófilos/metabolismo
Papio anubis
Proteína C/metabolismo
Receptores de Superfície Celular/imunologia
Receptores de Superfície Celular/metabolismo
Sepse/sangue
Sepse/imunologia
Acetato de Tetradecanoilforbol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (Endothelial Protein C Receptor); 0 (Macrophage-1 Antigen); 0 (PROCR protein, human); 0 (Protein C); 0 (Receptors, Cell Surface); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.768309


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[PMID]:28396322
[Au] Autor:Skopova K; Tomalova B; Kanchev I; Rossmann P; Svedova M; Adkins I; Bibova I; Tomala J; Masin J; Guiso N; Osicka R; Sedlacek R; Kovar M; Sebo P
[Ad] Endereço:Institute of Microbiology of the CAS, v.v.i., Prague, Czech Republic.
[Ti] Título:Cyclic AMP-Elevating Capacity of Adenylate Cyclase Toxin-Hemolysin Is Sufficient for Lung Infection but Not for Full Virulence of Bordetella pertussis.
[So] Source:Infect Immun;85(6), 2017 Jun.
[Is] ISSN:1098-5522
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, α ß integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b ) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b cells. The nonhemolytic AC Hly bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC Hly mutant also infected mouse lungs as efficiently as the parental AC Hly strain. Hence, elevation of cAMP in CD11b cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of infections at higher inoculation doses (>10 CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.
[Mh] Termos MeSH primário: Toxina Adenilato Ciclase/metabolismo
Bordetella pertussis/patogenicidade
AMP Cíclico/metabolismo
Proteínas Hemolisinas/metabolismo
Antígeno de Macrófago 1/metabolismo
Coqueluche/microbiologia
[Mh] Termos MeSH secundário: Animais
Antígeno CD11b/metabolismo
Membrana Celular/metabolismo
Células Dendríticas/imunologia
Feminino
Pulmão/microbiologia
Pulmão/patologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Fagócitos/imunologia
Linfócitos T/imunologia
Virulência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylate Cyclase Toxin); 0 (CD11b Antigen); 0 (Hemolysin Proteins); 0 (Macrophage-1 Antigen); E0399OZS9N (Cyclic AMP)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE


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[PMID]:28389621
[Au] Autor:Akenhead ML; Fukuda S; Schmid-Schönbein GW; Shin HY
[Ad] Endereço:Department of Biomedical Engineering, University of Kentucky, Lexington, Kentucky, USA.
[Ti] Título:Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion.
[So] Source:J Leukoc Biol;102(1):117-126, 2017 Jul.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is compelling evidence that circulatory hemodynamics prevent neutrophil activation, including adhesion to microvessels, in the microcirculation. However, the underlying mechanism or mechanisms by which that mechanoregulation occurs remain unresolved. Here, we report evidence that exposure to fluid shear stress (FSS) promotes neutrophils to release cathepsin B (ctsB) and that this autocrine regulatory event is antiadhesive for neutrophils on endothelial surfaces through Mac1-selective regulation. We used a combined cell-engineering and immunocytochemistry approach to find that ctsB was capable of cleaving Mac1 integrins on neutrophils and demonstrated that this proteolysis alters their adhesive functions. Under no-flow conditions, ctsB enhanced neutrophil migration though a putative effect on pseudopod retraction rates. We also established a flow-based cell detachment assay to verify the role of ctsB in the control of neutrophil adhesion by fluid flow stimulation. Fluid flow promoted neutrophil detachment from platelet and endothelial layers that required ctsB, consistent with its fluid shear stress-induced release. Notably, compared with leukocytes from wild-type mice, those from ctsB-deficient (ctsB ) mice exhibited an impaired CD18 cleavage response to FSS, significantly elevated baseline levels of CD18 surface expression, and an enhanced adhesive capacity to mildly inflamed postcapillary venules. Taken together, the results of the present study support a role for ctsB in a hemodynamic control mechanism that is antiadhesive for leukocytes on endothelium. These results have implications in the pathogenesis of chronic inflammation, microvascular dysfunction, and cardiovascular diseases involving sustained neutrophil activation in the blood and microcirculation.
[Mh] Termos MeSH primário: Catepsina B/imunologia
Antígeno de Macrófago 1/imunologia
Ativação de Neutrófilo
Neutrófilos/imunologia
Resistência ao Cisalhamento
[Mh] Termos MeSH secundário: Animais
Catepsina B/genética
Adesão Celular/genética
Adesão Celular/imunologia
Movimento Celular/genética
Movimento Celular/imunologia
Feminino
Células HL-60
Células Endoteliais da Veia Umbilical Humana
Seres Humanos
Antígeno de Macrófago 1/genética
Masculino
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Macrophage-1 Antigen); EC 3.4.22.1 (CTSB protein, human); EC 3.4.22.1 (Cathepsin B); EC 3.4.22.1 (Ctsb protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170409
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.3A0716-317RR


  9 / 3494 MEDLINE  
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[PMID]:28298456
[Au] Autor:Czirr E; Castello NA; Mosher KI; Castellano JM; Hinkson IV; Lucin KM; Baeza-Raja B; Ryu JK; Li L; Farina SN; Belichenko NP; Longo FM; Akassoglou K; Britschgi M; Cirrito JR; Wyss-Coray T
[Ad] Endereço:Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
[Ti] Título:Microglial complement receptor 3 regulates brain Aß levels through secreted proteolytic activity.
[So] Source:J Exp Med;214(4):1081-1092, 2017 Apr 03.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent genetic evidence supports a link between microglia and the complement system in Alzheimer's disease (AD). In this study, we uncovered a novel role for the microglial complement receptor 3 (CR3) in the regulation of soluble ß-amyloid (Aß) clearance independent of phagocytosis. Unexpectedly, ablation of CR3 in human amyloid precursor protein-transgenic mice results in decreased, rather than increased, Aß accumulation. In line with these findings, cultured microglia lacking CR3 are more efficient than wild-type cells at degrading extracellular Aß by secreting enzymatic factors, including tissue plasminogen activator. Furthermore, a small molecule modulator of CR3 reduces soluble Aß levels and Aß half-life in brain interstitial fluid (ISF), as measured by in vivo microdialysis. These results suggest that CR3 limits Aß clearance from the ISF, illustrating a novel role for CR3 and microglia in brain Aß metabolism and defining a potential new therapeutic target in AD.
[Mh] Termos MeSH primário: Peptídeos beta-Amiloides/análise
Encéfalo/metabolismo
Antígeno de Macrófago 1/fisiologia
Microglia/fisiologia
[Mh] Termos MeSH secundário: Doença de Alzheimer/etiologia
Peptídeos beta-Amiloides/metabolismo
Precursor de Proteína beta-Amiloide/fisiologia
Animais
Benzoatos/farmacologia
Camundongos
Camundongos Endogâmicos C57BL
Proteólise
Tioidantoínas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid beta-Peptides); 0 (Amyloid beta-Protein Precursor); 0 (Benzoates); 0 (Macrophage-1 Antigen); 0 (Thiohydantoins); 0 (leukadherin-1)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170317
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20162011


  10 / 3494 MEDLINE  
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[PMID]:28283064
[Au] Autor:Boire A; Zou Y; Shieh J; Macalinao DG; Pentsova E; Massagué J
[Ad] Endereço:Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
[Ti] Título:Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis.
[So] Source:Cell;168(6):1101-1113.e13, 2017 Mar 09.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course. C3 expression in primary tumors was predictive of leptomeningeal relapse. Mechanistically, we found that cancer-cell-derived C3 activates the C3a receptor in the choroid plexus epithelium to disrupt the blood-CSF barrier. This effect allows plasma components, including amphiregulin, and other mitogens to enter the CSF and promote cancer cell growth. Pharmacologic interference with C3 signaling proved therapeutically beneficial in suppressing leptomeningeal metastasis in these preclinical models.
[Mh] Termos MeSH primário: Complemento C3/metabolismo
Neoplasias Meníngeas/secundário
Metástase Neoplásica/patologia
[Mh] Termos MeSH secundário: Animais
Neoplasias da Mama/patologia
Líquido Cefalorraquidiano
Plexo Corióideo/irrigação sanguínea
Complemento C3/genética
Seres Humanos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Neoplasias Pulmonares/patologia
Antígeno de Macrófago 1/metabolismo
Camundongos
Transdução de Sinais
Microambiente Tumoral
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Complement C3); 0 (Intercellular Signaling Peptides and Proteins); 0 (Macrophage-1 Antigen)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170312
[St] Status:MEDLINE



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