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2.
Int Immunol ; 31(5): 287-302, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30668715

RESUMO

Chemokine systems modulate inflammatory and immune responses in inflammatory bowel disease (IBD). The colons of IBD patients show increased levels of fractalkine (FKN) and high numbers of FKN receptor-positive (CX3CR1+) cells; however, the FKN-CX3CR1 axis's role in intestinal inflammation, especially in intravascular leukocyte behaviors, still remains unclear. Here, we show that interruption of the FKN-CX3CR1 axis by anti-FKN monoclonal antibody (mAb) ameliorates murine colitis through regulation of intravascular monocyte behaviors in murine colitis models. FKN expression was detectable in vascular endothelium and CX3CR1+ macrophages accumulated in the mucosal lamina propria and submucosa of the inflamed colons. CD115+ monocytes tethered to the venous endothelium and expressed pro-inflammatory mediators. The anti-FKN mAb improved colitis symptoms, markedly reduced pro-inflammatory factors in the colon, maintained blood vessel integrity and reduced tethered monocytes in the inflamed veins. Intravital imaging revealed that CD115+Gr-1low/- monocytes crawled on the apical surfaces of venous endothelium, and anti-FKN mAb rapidly dislodged the crawling monocytes and inhibited their patrolling behavior. These findings suggest that the FKN-CX3CR1 axis triggers the patrolling behavior of crawling monocytes on the venous endothelium of inflamed colons, and accelerates the subsequent leukocyte activation and infiltration by locally producing inflammatory cytokines and chemokines. The mAb also ameliorated symptoms in another IBD model, T-cell-transferred colitis. Blocking the FKN-CX3CR1 axis with an anti-FKN mAb considerably inhibits the colitis-triggered inflammatory cascades, which may be an alternative strategy to treat IBD.


Assuntos
Anticorpos Monoclonais/farmacologia , Receptor 1 de Quimiocina CX3C/antagonistas & inibidores , Quimiocina CX3CL1/antagonistas & inibidores , Colite/tratamento farmacológico , Monócitos/efeitos dos fármacos , Administração Retal , Animais , Anticorpos Monoclonais/imunologia , Receptor 1 de Quimiocina CX3C/imunologia , Quimiocina CX3CL1/imunologia , Colite/induzido quimicamente , Colite/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/imunologia , Oxazóis
3.
Arthritis Rheumatol ; 71(2): 222-231, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30079992

RESUMO

OBJECTIVE: To elucidate the role of the fractalkine (FKN)/CX3 CR1 pathway in joint destruction in rheumatoid arthritis. METHODS: We examined the effect of treatment with anti-mouse FKN (anti-mFKN) monoclonal antibody (mAb) on joint destruction and the migration of osteoclast precursors (OCPs) into the joint, using the collagen-induced arthritis (CIA) model. DBA/1 mice were immunized with bovine type II collagen to induce arthritis, and then treated with anti-mFKN mAb. Disease severity was monitored by arthritis score, and joint destruction was evaluated by soft x-ray and histologic analyses. Plasma levels of joint destruction markers were assessed by enzyme-linked immunosorbent assay. FKN expression on endothelial cells was detected by immunohistochemistry. Bone marrow-derived OCPs were labeled with fluorescein and transferred to mice with CIA, and the migration of the OCPs to the joints was then analyzed. RESULTS: Both prophylactic and therapeutic treatment with anti-mFKN mAb significantly decreased the arthritis and soft x-ray scores. Plasma levels of cartilage oligomeric matrix protein and matrix metalloproteinase 3 decreased after treatment with anti-mFKN mAb. Histologic analysis revealed that anti-mFKN mAb inhibited synovitis, pannus formation, and cartilage destruction, as well as suppressed bone damage, with a marked reduction in the number of tartrate-resistant acid phosphatase-positive osteoclasts. Anti-mFKN mAb strongly inhibited the migration of bone marrow-derived OCPs into the affected synovium. CONCLUSION: Anti-mFKN mAb notably ameliorates arthritis and joint destruction in the CIA model, as well as inhibits migration of OCPs into the synovium. These results suggest that inhibition of the FKN/CX3 CR1 pathway could be a novel strategy for treatment of both synovitis and joint destruction in rheumatoid arthritis.


Assuntos
Anticorpos Monoclonais/farmacologia , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Receptor 1 de Quimiocina CX3C/imunologia , Movimento Celular/efeitos dos fármacos , Quimiocina CX3CL1/antagonistas & inibidores , Osteoclastos/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Animais , Proteína de Matriz Oligomérica de Cartilagem/efeitos dos fármacos , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Cartilagem Articular/patologia , Quimiocina CX3CL1/imunologia , Metaloproteinase 3 da Matriz/efeitos dos fármacos , Metaloproteinase 3 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Osteoclastos/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia , Fosfatase Ácida Resistente a Tartarato/metabolismo
4.
Nat Commun ; 5: 3337, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24535035

RESUMO

In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and Olig1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.


Assuntos
Cerebelo/citologia , Neurônios GABAérgicos/citologia , Interneurônios/citologia , Células de Purkinje/citologia , Células-Tronco/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Cerebelo/metabolismo , Neurônios GABAérgicos/metabolismo , Imuno-Histoquímica , Interneurônios/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos , Células de Purkinje/metabolismo , Células-Tronco/metabolismo , Fatores de Transcrição/metabolismo
5.
Development ; 134(17): 3213-25, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17670789

RESUMO

Directed differentiation and purification of mesencephalic dopaminergic (mesDA) neurons from stem cells are crucial issues for realizing safe and efficient cell transplantation therapies for Parkinson's disease. Although recent studies have identified the factors that regulate mesDA neuron development, the mechanisms underlying mesDA neuron specification are not fully understood. Recently, it has been suggested that mesencephalic floor plate (FP) cells acquire neural progenitor characteristics to generate mesDA neurons. Here, we directly examined this in a fate mapping experiment using fluorescence-activated cell sorting (FACS) with an FP cell-specific surface marker, and demonstrate that mesencephalic FP cells have neurogenic activity and generate mesDA neurons in vitro. By contrast, sorted caudal FP cells have no neurogenic potential, as previously thought. Analysis of dreher mutant mice carrying a mutation in the Lmx1a locus and transgenic mice ectopically expressing Otx2 in caudal FP cells demonstrated that Otx2 determines anterior identity that confers neurogenic activity to FP cells and specifies a mesDA fate, at least in part through the induction of Lmx1a. We further show that FACS can isolate mesDA progenitors, a suitable transplantation material, from embryonic stem cell-derived neural cells. Our data provide insights into the mechanisms of specification and generation of mesDA neurons, and illustrate a useful cell replacement approach for Parkinson's disease.


Assuntos
Dopamina/metabolismo , Células-Tronco Embrionárias/citologia , Mesencéfalo/embriologia , Neurônios/citologia , Animais , Animais Geneticamente Modificados , Padronização Corporal/genética , Diferenciação Celular/genética , Movimento Celular , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/fisiologia , Proteínas com Homeodomínio LIM , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/metabolismo , Fatores de Transcrição Otx/genética , Fatores de Transcrição Otx/fisiologia , Ratos , Fatores de Transcrição
6.
J Immunol ; 177(12): 8512-21, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17142749

RESUMO

Rho family small GTP-binding proteins, including Rho, Rac, and Cdc42, are key determinants of cell movement and actin-dependent cytoskeletal morphogenesis. Rho GDP-dissociation inhibitor (GDI) alpha and Rho GDIbeta (or D4/Ly-GDI), closely related regulators for Rho proteins, are both expressed in hemopoietic cell lineages. Nevertheless, the functional contributions of Rho GDIs remain poorly understood in vivo. In this study, we report that combined disruption of both the Rho GDIalpha and Rho GDIbeta genes in mice resulted in reduction of marginal zone B cells in the spleen, retention of mature T cells in the thymic medulla, and a marked increase in eosinophil numbers. Furthermore, these mice showed lower CD3 expression and impaired CD3-mediated proliferation of T cells. While B cells showed slightly enhanced chemotactic migration in response to CXCL12, peripheral T cells showed markedly reduced chemotactic migration in response to CCL21 and CCL19 associated with decreased receptor levels of CCR7. Overall, Rho protein levels were reduced in the bone marrow, spleen, and thymus but sustained activation of the residual part of RhoA, Rac1, and Cdc42 was detected mainly in the bone marrow and spleen. Rho GDIalpha and Rho GDIbeta thus play synergistic roles in lymphocyte migration and development by modulating activation cycle of the Rho proteins in a lymphoid organ-specific manner.


Assuntos
Linfócitos B/fisiologia , Quimiotaxia , Inibidores de Dissociação do Nucleotídeo Guanina/fisiologia , Proteínas/fisiologia , Animais , Contagem de Células , Células Cultivadas , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Linfonodos/citologia , Masculino , Camundongos , Camundongos Endogâmicos , Antígenos de Histocompatibilidade Menor , Especificidade de Órgãos , Baço/citologia , Linfócitos T/fisiologia , Timo/citologia , Proteínas rho de Ligação ao GTP/metabolismo , Inibidor alfa de Dissociação do Nucleotídeo Guanina rho , Inibidor beta de Dissociação do Nucleotídeo Guanina rho , Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico
7.
J Biol Chem ; 278(30): 28167-72, 2003 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-12740392

RESUMO

Malignant transformation of cells causes disruption of cell-cell adhesion, enhancement of cell motility, and invasion into surrounding tissues. Nectins have both homophilic and heterophilic cell-cell adhesion activities and organize adherens junctions in cooperation with cadherins. We examined here whether Tage4, which was originally identified to be a gene overexpressed in colon carcinoma and has a domain structure similar to those of nectins, is involved in cell adhesion and/or migration. Tage4 heterophilically trans-interacted with nectin-3, but not homophilically with Tage4. Expression of Tage4 was markedly elevated in NIH3T3 cells transformed by an oncogenic Ki-Ras (V12Ras-NIH3T3 cells) as compared with that of wild-type NIH3T3 cells. trans-Interaction of Tage4 with nectin-3 enhanced motility of V12Ras-NIH3T3 cells. Tage4 did not bind afadin, a nectin- and actin filament-binding protein that connects nectins to the actin cytoskeleton and cadherins through catenins. Thus, Tage4 heterophilically trans-interacts with nectin-3 and regulates cell migration. Tage4 is tentatively re-named here nectin-like molecule-5 (necl-5) on the basis of its function and domain structure similar to those of nectins.


Assuntos
Antígenos de Neoplasias , Moléculas de Adesão Celular/metabolismo , Proteínas de Neoplasias , Células 3T3 , Animais , Adesão Celular , Movimento Celular , Clonagem Molecular , Citoesqueleto/metabolismo , DNA Complementar/metabolismo , Dimerização , Humanos , Cinesinas , Cinética , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/metabolismo , Miosinas , Nectinas , Filogenia , Plasmídeos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Ressonância de Plasmônio de Superfície , Fatores de Tempo , Transfecção
8.
J Endod ; 28(5): 371-4, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12026922

RESUMO

This survey was conducted to obtain answers to some basic questions regarding the timing of root canal obturation. A questionnaire was sent via e-mail to 738 randomly chosen United States endodontists listed in the 1998 to 1999 membership roster of the American Association of Endodontists. One hundred fifty-six replies were received. In pulpectomy cases, root canal obturation at the first visit was carried out by 55.8% of the responding endodontists; in infected root canal cases, the percentage was 34.4%. Of the responding endodontists, 34.2% indicated that their patients had experienced some trouble after root canal obturation at the first visit.


Assuntos
Visita a Consultório Médico/estatística & dados numéricos , Obturação do Canal Radicular/métodos , Infecções Bacterianas/terapia , Humanos , Complicações Pós-Operatórias/epidemiologia , Pulpectomia/métodos , Irrigantes do Canal Radicular/uso terapêutico , Obturação do Canal Radicular/efeitos adversos , Inquéritos e Questionários , Fatores de Tempo
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