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1.
Inflamm Bowel Dis ; 22(4): 763-73, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26963567

RESUMO

BACKGROUND: NOD2 mutations are associated with Crohn's disease (CD). Both CD (in human) and Nod2 deficiency (in mice) are characterized by increased mucosal CD4 T-cells, an altered permeability and a microbial dysbiosis. However, the respective roles of the gut epithelial and immune compartments on the phenotype are not known. METHODS: Microbial composition, epithelial peptide secretion, intestinal permeability, and immune cell composition of Peyer patches were studied in Nod2 knock-out mice transplanted with wild-type bone marrow cells and vice versa. RESULTS: The nonhematopoietic cells control the microbiota composition and epithelial secretion of mucins and antimicrobial peptides. These parameters are correlated with recurrent associations between bacterial species and luminal products. In contrast, Nod2 in the hematopoietic compartment regulates the epithelial permeability and the gut-associated lymphoid tissue independently of the bacterial composition. CONCLUSIONS: The immune system and the gut permeability in one hand and the microbial and epithelial peptide compositions in the other hand are separate couples of interdependent parameters, both controlled by Nod2 in either the hematopoietic or nonhematopoietic lineages.


Assuntos
Disbiose/microbiologia , Microbioma Gastrointestinal , Células-Tronco Hematopoéticas/microbiologia , Homeostase/fisiologia , Mucosa Intestinal/microbiologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Animais , Disbiose/metabolismo , Disbiose/patologia , Células-Tronco Hematopoéticas/metabolismo , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout
2.
Inflamm Bowel Dis ; 21(3): 543-55, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25659087

RESUMO

BACKGROUND: Ileal Crohn's disease is related to NOD2 mutations and to a gut barrier dysfunction. Pseudomonas fluorescens has also been associated with ileal Crohn's disease. The aim of this study was to determine the impact of P. fluorescens on the paracellular permeability in ileum and Peyer's patches. METHODS: To explore this question, in vivo and ex vivo experiments were performed in wild-type, Nod2, Nod2, and IL-1R mice together with in vitro analyses using the Caco-2 (epithelial) and the THP-1 (monocyte) human cell lines. RESULTS: Pseudomonas fluorescens increased the paracellular permeability of the intestinal mucosa through the secretion of IL-1ß by the immune cell populations and the activation of myosin light chain kinase in the epithelial cells. Induction of the IL-1ß pathway required the expression of Nod2 in the hematopoietic compartment, and muramyl dipeptide (a Nod2 ligand) had an inhibitory effect. CONCLUSIONS: Pseudomonas fluorescens thus alters the homeostasis of the epithelial barrier function by a mechanism similar to that previously observed for Yersinia pseudotuberculosis. This work further documents a putative role of psychrotrophic bacteria in Crohn's disease.


Assuntos
Células-Tronco Hematopoéticas/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Proteína Adaptadora de Sinalização NOD2/fisiologia , Pseudomonas fluorescens/fisiologia , Receptores de Interleucina-1/fisiologia , Animais , Western Blotting , Células CACO-2 , Permeabilidade da Membrana Celular , Células Cultivadas , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/microbiologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/microbiologia , Macrófagos/citologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais
3.
Arch Microbiol ; 195(3): 189-95, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23306900

RESUMO

The effect of intestinal molecules produced by the host on the virulence of Pseudomonas fluorescens is poorly documented. In the present work, we evaluated the secretion of human ß-defensin-2 (hBD-2) by enterocytes after infection with P. fluorescens (a species previously suggested to be involved in inflammatory bowel disease) and investigated the effect of this host-defense peptide on the bacterial virulence. The results showed that P. fluorescens can induce hBD-2 production in Caco-2/TC7 cells via P38 and ERK MAPK-dependent pathways. Surprisingly, the exposure of P. fluorescens to low doses of the antimicrobial peptide was found to enhance its cytotoxic and proinflammatory effects suggesting a potential feedback mechanism in the dialog between bacteria and the host.


Assuntos
Células Epiteliais/microbiologia , Pseudomonas fluorescens/metabolismo , Pseudomonas fluorescens/patogenicidade , beta-Defensinas/metabolismo , Anti-Infecciosos/metabolismo , Anti-Infecciosos/farmacologia , Células CACO-2 , Enterócitos/metabolismo , Enterócitos/microbiologia , Células Epiteliais/metabolismo , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/metabolismo , Pseudomonas fluorescens/efeitos dos fármacos , Virulência/fisiologia , beta-Defensinas/farmacologia
4.
J Clin Invest ; 122(6): 2239-51, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22565313

RESUMO

Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer's patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis-infected monocytes activated caspase-1 and produced IL-1ß. In turn, IL-1ß increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.


Assuntos
Células-Tronco Hematopoéticas/imunologia , Mucosa Intestinal/imunologia , Nódulos Linfáticos Agregados/imunologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Yersinia pseudotuberculosis/imunologia , Animais , Células CACO-2 , Caspase 1/genética , Caspase 1/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Células-Tronco Hematopoéticas/microbiologia , Células-Tronco Hematopoéticas/patologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/patologia , Transdução de Sinais/genética , Receptor 2 Toll-Like/genética , Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/patologia
5.
Cell Host Microbe ; 11(4): 337-51, 2012 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-22520462

RESUMO

Yersinia pseudotuberculosis is an enteropathogenic bacteria that disrupts the intestinal barrier and invades its host through gut-associated lymphoid tissue and Peyer's patches (PP). We show that the Y. pseudotuberculosis effector YopJ induces intestinal barrier dysfunction by subverting signaling of the innate immune receptor Nod2, a phenotype that can be reversed by pretreating with the Nod2 ligand muramyl-dipeptide. YopJ, but not the catalytically inactive mutant YopJ(C172A), acetylates critical sites in the activation loops of the RICK and TAK1 kinases, which are central mediators of Nod2 signaling, and decreases the affinity of Nod2 for RICK. Concomitantly, Nod2 interacts with and activates caspase-1, resulting in increased levels of IL-1ß. Finally, IL-1ß within PP plays an essential role in inducing intestinal barrier dysfunction. Thus, YopJ alters intestinal permeability and promotes the dissemination of Yersinia as well as commensal bacteria by exploiting the mucosal inflammatory response.


Assuntos
Proteínas de Bactérias/metabolismo , Caspase 1/metabolismo , Intestinos/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Infecções por Yersinia pseudotuberculosis/enzimologia , Yersinia pseudotuberculosis/metabolismo , Animais , Proteínas de Bactérias/genética , Caspase 1/genética , Linhagem Celular , Feminino , Humanos , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Transdução de Sinais , Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/metabolismo , Infecções por Yersinia pseudotuberculosis/microbiologia
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