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1.
Blood ; 129(11): 1503-1513, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28087538

RESUMO

B-cell adaptor for phosphatidylinositol 3-kinase (BCAP) is a signaling adaptor expressed in mature hematopoietic cells, including monocytes and neutrophils. Here we investigated the role of BCAP in the homeostasis and development of these myeloid lineages. BCAP-/- mice had more bone marrow (BM) monocytes than wild-type (WT) mice, and in mixed WT:BCAP-/- BM chimeras, monocytes and neutrophils skewed toward BCAP-/- origin, showing a competitive advantage for BCAP-/- myeloid cells. BCAP was expressed in BM hematopoietic progenitors, including lineage-Sca-1+c-kit+ (LSK), common myeloid progenitor, and granulocyte/macrophage progenitor (GMP) cells. At the steady state, BCAP-/- GMP cells expressed more IRF8 and less C/EBPα than did WT GMP cells, which correlated with an increase in monocyte progenitors and a decrease in granulocyte progenitors among GMP cells. Strikingly, BCAP-/- progenitors proliferated and produced more myeloid cells of both neutrophil and monocyte/macrophage lineages than did WT progenitors in myeloid colony-forming unit assays, supporting a cell-intrinsic role of BCAP in inhibiting myeloid proliferation and differentiation. Consistent with these findings, during cyclophosphamide-induced myeloablation or specific monocyte depletion, BCAP-/- mice replenished circulating monocytes and neutrophils earlier than WT mice. During myeloid replenishment after cyclophosphamide-induced myeloablation, BCAP-/- mice had increased LSK proliferation and increased numbers of LSK and GMP cells compared with WT mice. Furthermore, BCAP-/- mice accumulated more monocytes and neutrophils in the spleen than did WT mice during Listeria monocytogenes infection. Together, these data identify BCAP as a novel inhibitor of myelopoiesis in the steady state and of emergency myelopoiesis during demand conditions.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Diferenciação Celular , Proliferação de Células , Células Progenitoras Mieloides/citologia , Animais , Linhagem da Célula , Homeostase , Camundongos , Monócitos/citologia , Mielopoese , Neutrófilos/citologia
2.
J Immunol ; 186(10): 5916-26, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21482737

RESUMO

Infectious pneumonias exact an unacceptable mortality burden worldwide. Efforts to protect populations from pneumonia have focused historically on antibiotic development and vaccine-enhanced adaptive immunity. However, we have reported recently that the lungs' innate defenses can be induced therapeutically by inhalation of a bacterial lysate that protects mice against otherwise lethal pneumonia. In this study, we tested in mice the hypothesis that TLRs are required for this antimicrobial phenomenon and found that resistance could not be induced in the absence of the TLR signaling adaptor protein MyD88. We then attempted to recapitulate the protection afforded by the bacterial lysate by stimulating the lung epithelium with aerosolized synthetic TLR ligands. Although most single or combination treatments yielded no protection, simultaneous treatment with ligands for TLR2/6 and TLR9 conferred robust, synergistic protection against virulent gram-positive and gram-negative pathogens. Protection was associated with rapid pathogen killing in the lungs, and pathogen killing could be induced from lung epithelial cells in isolation. Taken together, these data demonstrate the requirement for TLRs in inducible resistance against pneumonia, reveal a remarkable, unanticipated synergistic interaction of TLR2/6 and TLR9, reinforce the emerging evidence supporting the antimicrobial capacity of the lung epithelium, and may provide the basis for a novel clinical therapeutic that can protect patients against pneumonia during periods of peak vulnerability.


Assuntos
Pneumonia Bacteriana/imunologia , Pneumonia Pneumocócica/imunologia , Infecções por Pseudomonas/imunologia , Receptor 2 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Células Epiteliais/imunologia , Feminino , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Pneumonia Bacteriana/microbiologia , Pneumonia Pneumocócica/microbiologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/imunologia , Receptor 6 Toll-Like/agonistas , Receptor 6 Toll-Like/imunologia , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/imunologia
3.
Sci Signal ; 12(581)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088976

RESUMO

B cell adaptor for phosphoinositide 3-kinase (PI3K) (BCAP) is a signaling adaptor that activates the PI3K pathway downstream of B cell receptor signaling in B cells and Toll-like receptor (TLR) signaling in macrophages. BCAP binds to the regulatory p85 subunit of class I PI3K and is a large, multidomain protein. We used proteomic analysis to identify other BCAP-interacting proteins in macrophages and found that BCAP specifically associated with the caspase-1 pseudosubstrate inhibitor Flightless-1 and its binding partner leucine-rich repeat flightless-interacting protein 2. Because these proteins inhibit the NLRP3 inflammasome, we investigated the role of BCAP in inflammasome function. Independent of its effects on TLR priming, BCAP inhibited NLRP3- and NLRC4-induced caspase-1 activation, cell death, and IL-1ß release from macrophages. Accordingly, caspase-1-dependent clearance of a Yersinia pseudotuberculosis mutant was enhanced in BCAP-deficient mice. Mechanistically, BCAP delayed the recruitment and activation of pro-caspase-1 within the NLRP3/ASC preinflammasome through its association with Flightless-1. Thus, BCAP is a multifunctional signaling adaptor that inhibits key pathogen-sensing pathways in macrophages.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Inflamassomos/metabolismo , Macrófagos/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Caspase 1/genética , Caspase 1/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Macrófagos/microbiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Ligação Proteica , Yersinia pseudotuberculosis/genética , Yersinia pseudotuberculosis/fisiologia
4.
Science ; 363(6423)2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30630901

RESUMO

Cytopenias are an important clinical problem associated with inflammatory disease and infection. We show that specialized phagocytes that internalize red blood cells develop in Toll-like receptor 7 (TLR7)-driven inflammation. TLR7 signaling caused the development of inflammatory hemophagocytes (iHPCs), which resemble splenic red pulp macrophages but are a distinct population derived from Ly6Chi monocytes. iHPCs were responsible for anemia and thrombocytopenia in TLR7-overexpressing mice, which have a macrophage activation syndrome (MAS)-like disease. Interferon regulatory factor 5 (IRF5), associated with MAS, participated in TLR7-driven iHPC differentiation. We also found iHPCs during experimental malarial anemia, in which they required endosomal TLR and MyD88 signaling for differentiation. Our findings uncover a mechanism by which TLR7 and TLR9 specify monocyte fate and identify a specialized population of phagocytes responsible for anemia and thrombocytopenia associated with inflammation and infection.


Assuntos
Anemia/fisiopatologia , Síndrome de Ativação Macrofágica/fisiopatologia , Glicoproteínas de Membrana/fisiologia , Fagócitos/citologia , Transdução de Sinais , Receptor 7 Toll-Like/fisiologia , Receptor Toll-Like 9/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Proteínas de Ligação a DNA/fisiologia , Inflamação/fisiopatologia , Fatores Reguladores de Interferon/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/citologia , Fator 88 de Diferenciação Mieloide/fisiologia , Plasmodium yoelii , Baço/citologia , Trombocitopenia/fisiopatologia , Transcriptoma
5.
Diabetes ; 67(5): 946-959, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29483182

RESUMO

Cardiovascular disease caused by atherosclerosis is the leading cause of mortality associated with type 2 diabetes and metabolic syndrome. Insulin therapy is often needed to improve glycemic control, but it does not clearly prevent atherosclerosis. Upon binding to the insulin receptor (IR), insulin activates distinct arms of downstream signaling. The IR-Akt arm is associated with blood glucose lowering and beneficial effects, whereas the IR-Erk arm might exert less desirable effects. We investigated whether selective activation of the IR-Akt arm, leaving the IR-Erk arm largely inactive, would result in protection from atherosclerosis in a mouse model of metabolic syndrome. The insulin mimetic peptide S597 lowered blood glucose and activated Akt in insulin target tissues, mimicking insulin's effects, but only weakly activated Erk and even prevented insulin-induced Erk activation. Strikingly, S597 retarded atherosclerotic lesion progression through a process associated with protection from leukocytosis, thereby reducing lesional accumulation of inflammatory Ly6Chi monocytes. S597-mediated protection from leukocytosis was accompanied by reduced numbers of the earliest bone marrow hematopoietic stem cells and reduced IR-Erk activity in hematopoietic stem cells. This study provides a conceptually novel treatment strategy for advanced atherosclerosis associated with metabolic syndrome and type 2 diabetes.


Assuntos
Aterosclerose/prevenção & controle , Glicemia/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Síndrome Metabólica/tratamento farmacológico , Peptídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Receptor de Insulina/efeitos dos fármacos , Animais , Aterosclerose/etiologia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/prevenção & controle , Modelos Animais de Doenças , Masculino , Síndrome Metabólica/complicações , Camundongos , Camundongos Knockout , Monócitos , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/agonistas , Receptor de Insulina/metabolismo , Receptores de LDL/genética , Transdução de Sinais
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