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1.
Proc Natl Acad Sci U S A ; 110(5): 1726-31, 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23322734

RESUMO

The metabolism of membrane phosphoinositides is critical for a variety of cellular processes. Phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P(2)] controls multiple steps of the intracellular membrane trafficking system in both yeast and mammalian cells. However, other than in neuronal tissues, little is known about the physiological functions of PtdIns(3,5)P(2) in mammals. Here, we provide genetic evidence that type III phosphatidylinositol phosphate kinase (PIPKIII), which produces PtdIns(3,5)P(2), is essential for the functions of polarized epithelial cells. PIPKIII-null mouse embryos die by embryonic day 8.5 because of a failure of the visceral endoderm to supply the epiblast with maternal nutrients. Similarly, although intestine-specific PIPKIII-deficient mice are born, they fail to thrive and eventually die of malnutrition. At the mechanistic level, we show that PIPKIII regulates the trafficking of proteins to a cell's apical membrane domain. Importantly, mice with intestine-specific deletion of PIPKIII exhibit diarrhea and bloody stool, and their gut epithelial layers show inflammation and fibrosis, making our mutants an improved model for inflammatory bowel diseases. In summary, our data demonstrate that PIPKIII is required for the structural and functional integrity of two different types of polarized epithelial cells and suggest that PtdIns(3,5)P(2) metabolism is an unexpected and critical link between membrane trafficking in intestinal epithelial cells and the pathogenesis of inflammatory bowel disease.


Assuntos
Endoderma/metabolismo , Mucosa Intestinal/metabolismo , Fosfatidilinositol 3-Quinases/genética , Vísceras/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/ultraestrutura , Células-Tronco Embrionárias/metabolismo , Endoderma/embriologia , Endoderma/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Intestinos/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica , Análise de Sequência com Séries de Oligonucleotídeos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Vísceras/embriologia , Vísceras/ultraestrutura
2.
Am J Respir Crit Care Med ; 187(1): 65-77, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23144331

RESUMO

RATIONALE: Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome-coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation. OBJECTIVES: We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins. METHODS: We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/ß receptor 1), or TIR domain-containing adaptor inducing IFN-ß (TRIF). MEASUREMENTS AND MAIN RESULTS: We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a unique CXCR3 receptor via TRIF. CXCL10-CXCR3 acts in an autocrine fashion on the oxidative burst and chemotaxis in the inflamed neutrophils, leading to fulminant pulmonary inflammation. CONCLUSIONS: CXCL10-CXCR3 signaling appears to be a critical factor for the exacerbation of the pathology of ARDS. Thus, the CXCL10-CXCR3 axis could represent a prime therapeutic target in the treatment of the acute phase of ARDS of nonviral and viral origins.


Assuntos
Quimiocina CXCL10/fisiologia , Lesão Pulmonar/fisiopatologia , Neutrófilos/fisiologia , Infecções por Orthomyxoviridae/fisiopatologia , Receptores CXCR3/fisiologia , Síndrome do Desconforto Respiratório/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Animais , Quimiocina CXCL10/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Humanos , Virus da Influenza A Subtipo H5N1 , Lesão Pulmonar/imunologia , Lesão Pulmonar/virologia , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Neutrófilos/imunologia , Infecções por Orthomyxoviridae/imunologia , Análise Serial de Proteínas , Ratos , Ratos Sprague-Dawley , Receptores CXCR3/efeitos dos fármacos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/imunologia , Síndrome do Desconforto Respiratório/virologia
3.
Nature ; 465(7297): 497-501, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20463662

RESUMO

Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation. Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P(2) phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, Inpp4a(-/-) mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-d-aspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)P(2), PtdIns(3,4,5)P(3) and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)P(2) metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)P(2) metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.


Assuntos
Ácido Glutâmico/toxicidade , Neurônios/citologia , Neurônios/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Regulação para Baixo , Discinesias/genética , Discinesias/patologia , Discinesias/fisiopatologia , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neostriado/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Neurônios/enzimologia , Neurônios/patologia , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Taxa de Sobrevida , Sinapses/metabolismo , Redução de Peso
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