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1.
J Virol ; 92(3)2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29142134

RESUMO

Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169+ cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169+ cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b+ Ly6C+ Ly6G+ cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169+ cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169+ cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169+ cells and innate and adaptive immune activation during VSV infection.IMPORTANCE Over the last decade, strategically placed CD169+ metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169+ macrophages have been shown to activate innate and adaptive immunity via "enforced virus replication," a controlled amplification of virus particles. However, the factors regulating the CD169+ macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169+ macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.


Assuntos
Interferon Tipo I/imunologia , Macrófagos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Estomatite Vesicular/imunologia , Imunidade Adaptativa , Animais , Imunidade Inata , Macrófagos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico , Fator de Transcrição RelA/metabolismo , Vesiculovirus/fisiologia , Replicação Viral
2.
Proc Natl Acad Sci U S A ; 112(17): 5521-6, 2015 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-25870278

RESUMO

Urea cycle defects and acute or chronic liver failure are linked to systemic hyperammonemia and often result in cerebral dysfunction and encephalopathy. Although an important role of the liver in ammonia metabolism is widely accepted, the role of ammonia metabolizing pathways in the liver for maintenance of whole-body ammonia homeostasis in vivo remains ill-defined. Here, we show by generation of liver-specific Gln synthetase (GS)-deficient mice that GS in the liver is critically involved in systemic ammonia homeostasis in vivo. Hepatic deletion of GS triggered systemic hyperammonemia, which was associated with cerebral oxidative stress as indicated by increased levels of oxidized RNA and enhanced protein Tyr nitration. Liver-specific GS-deficient mice showed increased locomotion, impaired fear memory, and a slightly reduced life span. In conclusion, the present observations highlight the importance of hepatic GS for maintenance of ammonia homeostasis and establish the liver-specific GS KO mouse as a model with which to study effects of chronic hyperammonemia.


Assuntos
Glutamato-Amônia Ligase/metabolismo , Hiperamonemia/enzimologia , Fígado/enzimologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Marcação de Genes , Glutamato-Amônia Ligase/genética , Hiperamonemia/genética , Hiperamonemia/patologia , Hiperamonemia/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Locomoção , Memória , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética
3.
Eur J Immunol ; 45(2): 418-27, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25393615

RESUMO

STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent viruses. In this study, we investigate how T-cell functions of STAT3 contribute to responses to viral infection by inducing chronic lymphocytic choriomeningitis virus (LCMV) infection in mice lacking STAT3 specifically in T cells. Although mice with conditional disruption of STAT3 in T cells were able to mount early responses to viral infection similar to control animals, including expansion of effector T cells, we found generation of T-follicular helper (Tfh) cells to be impaired. As a result, STAT3 T cell deficient mice produced attenuated germinal center reactions, and did not accumulate bone marrow virus specific IgG-secreting cells, resulting in failure to maintain levels of virus-specific IgG or mount neutralizing responses to LCMV in the serum. These effects were associated with reduced control of viral replication and prolonged infection. Our results demonstrate the importance of STAT3 in T cells for the generation of functional long-term humoral immunity to viral infections.


Assuntos
Anticorpos Antivirais/biossíntese , Imunidade Humoral , Imunoglobulina G/biossíntese , Coriomeningite Linfocítica/imunologia , Fator de Transcrição STAT3/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos B/virologia , Doença Crônica , Expressão Gênica , Imunofenotipagem , Coriomeningite Linfocítica/genética , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Knockout , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Citotóxicos/virologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/virologia , Replicação Viral
4.
Cell Physiol Biochem ; 38(4): 1500-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27050423

RESUMO

BACKGROUND/AIMS: In nucleated cells, bile acids may activate cation channels subsequently leading to entry of Ca2+. In erythrocytes, increase of cytosolic Ca2+ activity triggers eryptosis, the suicidal death of erythrocytes characterized by phosphatidylserine exposure at the cell surface and cell shrinkage. Eryptosis is triggered by bile duct ligation, an effect partially attributed to conjugated bilirubin. The present study explored, whether bile acids may stimulate eryptosis. METHODS: Phosphatidylserine exposing erythrocytes have been identified utilizing annexin V binding, cell volume estimated from forward scatter, cytosolic Ca2+ activity determined using Fluo-3 fluorescence, and ceramide abundance at the erythrocyte surface utilizing specific antibodies. RESULTS: The exposure of human erythrocytes to glycochenodesoxycholic (GCDC) and taurochenodesoxycholic (TCDC) acid was followed by a significant decrease of forward scatter and significant increase of Fluo-3 fluorescence, ceramide abundance as well as annexin V binding. The effect on annexin V binding was significantly blunted, but not abolished by removal of extracellular Ca2+. CONCLUSION: Bile acids stimulate suicidal cell death, an effect paralleled by and in part due to Ca2+ entry and ceramide. The bile acid induced eryptosis may in turn lead to accelerated clearance of circulating erythrocytes and, thus, may contribute to anemia in cholestatic patients.


Assuntos
Ácidos e Sais Biliares/toxicidade , Eriptose/efeitos dos fármacos , Compostos de Anilina/química , Compostos de Anilina/metabolismo , Cálcio/metabolismo , Células Cultivadas , Ceramidas/metabolismo , Colagogos e Coleréticos/farmacologia , Detergentes/farmacologia , Eritrócitos/citologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Citometria de Fluxo , Ácido Glicoquenodesoxicólico/toxicidade , Hemólise/efeitos dos fármacos , Humanos , Fosfatidilserinas/metabolismo , Ácido Tauroquenodesoxicólico/toxicidade , Xantenos/química , Xantenos/metabolismo
5.
Cell Physiol Biochem ; 39(2): 668-76, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27442519

RESUMO

BACKGROUND/AIMS: Similar to apoptosis of nucleated cells, red blood cells (RBC) can undergo suicidal cell death - called eryptosis. It is characterized by cell shrinkage and phosphatidylserine translocation. Eryptosis is triggered by an increase of intracellular calcium concentration due to activation of nonselective cation channels. The cation channels and consequently eryptosis are inhibited by erythropoietin. Eryptotic RBC are engulfed by macrophages and thus rapidly cleared from circulating blood. In this study, we explored whether storage of RBC influences the rate of eryptosis. METHODS: Flow cytometry was employed to quantify phosphatidylserine exposing erythrocytes from annexin V binding and cytosolic Ca2+ activity from Fluo-3 fluorescence. Clearance of stored murine RBC was tested by injection of carboxyfluorescein succinimidyl ester (CFSE)-labelled erythrocytes. RESULTS: Storage for 42 days significantly increased the percentage of phosphatidylserine exposing and haemolytic erythrocytes, an effect blunted by removal of extracellular calcium. Phosphatidylserine exposure could be inhibited by addition of erythropoietin. Upon transfusion, the clearance of murine CFSE-labelled RBC from circulating blood was significantly higher following storage for 10 days when compared to 2 days of storage. CONCLUSION: Storage of RBC triggers eryptosis by Ca2+ and erythropoietin sensitive mechanisms.


Assuntos
Apoptose/fisiologia , Preservação de Sangue/métodos , Eriptose/fisiologia , Eritrócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Eriptose/efeitos dos fármacos , Eritrócitos/química , Eritrócitos/citologia , Eritropoetina/farmacologia , Citometria de Fluxo/métodos , Fluoresceínas/química , Humanos , Espaço Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Fosfatidilserinas/metabolismo , Succinimidas/química , Fatores de Tempo
6.
Cell Physiol Biochem ; 39(4): 1271-80, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27606466

RESUMO

BACKGROUND/AIMS: Viral infections represent a global health problem with the need for new viral therapies and better understanding of the immune response during infection. The most immediate and potent anti-viral defense mechanism is the production of type I interferon (IFN-I) which are activated rapidly following recognition of viral infection by host pathogen recognition receptors (PRR). The mechanisms of innate cellular signaling downstream of PRR activation remain to be fully understood. In the present study, we demonstrate that CASP2 and RIPK1 domain-containing adaptor with death domain (CRADD/RAIDD) is a critical component in type I IFN production. METHODS: The role of RAIDD during IFN-I production was investigated using western blot, shRNA mediated lentiviral knockdown, immunoprecipitation and IFN-I driven dual luciferase assay. RESULTS: Immunoprecipitation analysis revealed the molecular interaction of RAIDD with interferon regulatory factor 7 (IRF7) and its phosphorylating kinase IKKε. Using an IFN-4α driven dual luciferase analysis in RAIDD deficient cells, type I IFN activation by IKKε and IRF7 was dramatically reduced. Furthermore, deletion of either the caspase recruitment domain (CARD) or death domain (DD) of RAIDD inhibited IKKε and IRF7 mediated interferon-4α activation. CONCLUSION: We have identified that the adaptor molecule RAIDD coordinates IKKε and IRF7 interaction to ensure efficient expression of type I interferon.


Assuntos
Proteína Adaptadora de Sinalização CRADD/genética , Quinase I-kappa B/genética , Fator Regulador 7 de Interferon/genética , Receptor 3 Toll-Like/genética , Animais , Proteína Adaptadora de Sinalização CRADD/imunologia , Domínio de Ativação e Recrutamento de Caspases , Regulação da Expressão Gênica , Genes Reporter , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HEK293 , Humanos , Quinase I-kappa B/imunologia , Fator Regulador 7 de Interferon/imunologia , Interferon-alfa/genética , Interferon-alfa/imunologia , Interferon beta/genética , Interferon beta/imunologia , Lentivirus/genética , Lentivirus/metabolismo , Luciferases/genética , Luciferases/metabolismo , Camundongos , Plasmídeos/química , Plasmídeos/metabolismo , Poli I-C/farmacologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Transdução de Sinais , Receptor 3 Toll-Like/imunologia
7.
Proc Natl Acad Sci U S A ; 110(7): 2593-8, 2013 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-23359703

RESUMO

Rapid activation of immune responses is necessary for antibacterial defense, but excessive immune activation can result in life-threatening septic shock. Understanding how these processes are balanced may provide novel therapeutic potential in treating inflammatory disease. Fc receptors are crucial for innate immune activation. However, the role of the putative Fc receptor for IgM, known as Toso/Faim3, has to this point been unclear. In this study, we generated Toso-deficient mice and used them to uncover a critical regulatory function of Toso in innate immune activation. Development of innate immune cells was intact in the absence of Toso, but Toso-deficient neutrophils exhibited more reactive oxygen species production and reduced phagocytosis of pathogens compared with controls. Cytokine production was also decreased in Toso(-/-) mice compared with WT animals, rendering them resistant to septic shock induced by lipopolysaccharide. However, Toso(-/-) mice also displayed limited cytokine production after infection with the bacterium Listeria monocytogenes that was correlated with elevated presence of Listeria throughout the body. Accordingly, Toso(-/-) mice succumbed to infections of L. monocytogenes, whereas WT mice successfully eliminated the infection. Taken together, our data reveal Toso to be a unique regulator of innate immune responses during bacterial infection and septic shock.


Assuntos
Proteínas de Transporte/imunologia , Granulócitos/imunologia , Imunidade Inata/imunologia , Listeriose/imunologia , Ativação de Macrófagos/imunologia , Proteínas de Membrana/imunologia , Monócitos/imunologia , Análise de Variância , Animais , Proteínas de Transporte/genética , Cruzamentos Genéticos , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Peroxidase/metabolismo , Fagocitose/imunologia , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
8.
Cell Rep ; 42(9): 113034, 2023 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-37651228

RESUMO

Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.


Assuntos
Glioblastoma , Metabolismo dos Lipídeos , Humanos , Formiatos , Invasividade Neoplásica , Microambiente Tumoral
9.
Nat Commun ; 13(1): 2699, 2022 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-35577770

RESUMO

Metastasis is the most common cause of death in cancer patients. Canonical drugs target mainly the proliferative capacity of cancer cells, which leaves slow-proliferating, persistent cancer cells unaffected. Metabolic determinants that contribute to growth-independent functions are still poorly understood. Here we show that antifolate treatment results in an uncoupled and autarkic mitochondrial one-carbon (1C) metabolism during cytosolic 1C metabolism impairment. Interestingly, antifolate dependent growth-arrest does not correlate with decreased migration capacity. Therefore, using methotrexate as a tool compound allows us to disentangle proliferation and migration to profile the metabolic phenotype of migrating cells. We observe that increased serine de novo synthesis (SSP) supports mitochondrial serine catabolism and inhibition of SSP using the competitive PHGDH-inhibitor BI-4916 reduces cancer cell migration. Furthermore, we show that sole inhibition of mitochondrial serine catabolism does not affect primary breast tumor growth but strongly inhibits pulmonary metastasis. We conclude that mitochondrial 1C metabolism, despite being dispensable for proliferative capacities, confers an advantage to cancer cells by supporting their motility potential.


Assuntos
Neoplasias da Mama , Antagonistas do Ácido Fólico , Neoplasias da Mama/metabolismo , Ciclo do Carbono , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Mitocôndrias/metabolismo , Serina/metabolismo
10.
Autophagy ; 16(8): 1436-1452, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31775562

RESUMO

In solid tumors, cancer stem cells (CSCs) or tumor-initiating cells (TICs) are often found in hypoxic niches. Nevertheless, the influence of hypoxia on TICs is poorly understood. Using previously established, TIC-enrichedpatient-derived colorectal cancer (CRC) cultures, we show that hypoxia increases the self-renewal capacity of TICs while inducing proliferation arrest in their more differentiated counterpart cultures. Gene expression data revealed macroautophagy/autophagy as one of the major pathways induced by hypoxia in TICs. Interestingly, hypoxia-induced autophagy was found to induce phosphorylation of EZR (ezrin) at Thr567 residue, which could be reversed by knocking down ATG5, BNIP3, BNIP3L, or BECN1. Furthermore, we identified PRKCA/PKCα as a potential kinase involved in hypoxia-induced autophagy-mediated TIC self-renewal. Genetic targeting of autophagy or pharmacological inhibition of PRKC/PKC and EZR resulted in decreased tumor-initiating potential of TICs. In addition, we observed significantly reduced in vivo tumor initiation and growth after a stable knockdown of ATG5. Analysis of human CRC samples showed that p-EZR is often present in TICs located in the hypoxic and autophagic regions of the tumor. Altogether, our results establish the hypoxia-autophagy-PKC-EZR signaling axis as a novel regulatory mechanism of TIC self-renewal and CRC progression. Autophagy inhibition might thus represent a promising therapeutic strategy for cancer patients. ABBREVIATIONS: ATG: autophagy related; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CQ: chloroquine; CSC: cancer stem cells; CRC: colorectal cancer; HIF1A/HIF-1α: hypoxia inducible factor 1 subunit alpha; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PRKC/PKC: protein kinase C; SQSTM1/p62: sequestosome 1; TICs: tumor-initiating cells.


Assuntos
Carcinogênese/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Hipóxia/complicações , Proteína Quinase C/metabolismo , Transdução de Sinais , Animais , Autofagossomos/metabolismo , Autofagia , Proteína 5 Relacionada à Autofagia/deficiência , Proteína 5 Relacionada à Autofagia/metabolismo , Autorrenovação Celular , Colo/patologia , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , Fosforilação
11.
Artigo em Inglês | MEDLINE | ID: mdl-32117809

RESUMO

Elucidating key factors that regulate immune-mediated pathology in vivo is critical for developing improved strategies to treat autoimmune disease and cancer. NK cells can exhibit regulatory functions against CD8+ T cells following viral infection. Here we show that while low doses of lymphocytic choriomeningitis virus (LCMV-WE) can readily induce strong CD8+ T cell responses and diabetes in mice expressing the LCMV glycoprotein on ß-islet cells (RIP-GP mice), hyperglycemia does not occur after infection with higher doses of LCMV. High-dose LCMV infection induced an impaired CD8+ T cell response, which coincided with increased NK cell activity during early time points following infection. Notably, we observed increased NKp46 expression on NK cells during infection with higher doses, which resulted in an NK cell dependent suppression of T cells. Accordingly, depletion with antibodies specific for NK1.1 as well as NKp46 deficiency (Ncr1gfp/gfp mice) could restore CD8+ T cell immunity and permitted the induction of diabetes even following infection of RIP-GP mice with high-dose LCMV. Therefore, we identify conditions where innate lymphoid cells can play a regulatory role and interfere with CD8+ T cell mediated tissue specific pathology using an NKp46 dependent mechanism.


Assuntos
Coriomeningite Linfocítica , Animais , Autoimunidade , Linfócitos T CD8-Positivos , Imunidade Inata , Células Matadoras Naturais , Camundongos , Camundongos Endogâmicos C57BL
12.
Front Immunol ; 10: 1848, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440242

RESUMO

Cancer cells utilize multiple mechanisms to evade and suppress anticancer immune responses creating a "cold" immunosuppressive tumor microenvironment. Oncolytic virotherapy is emerging as a promising approach to revert tumor immunosuppression and enhance the efficacy of other forms of immunotherapy. Growing evidence indicates that oncolytic viruses (OVs) act in a multimodal fashion, inducing immunogenic cell death and thereby eliciting robust anticancer immune responses. In this review, we summarize information about OV-mediated immune conversion of the tumor microenvironment. As a case study we focus on the rodent protoparvovirus H-1PV and its dual role as an oncolytic and immune modulatory agent. Potential strategies to improve H-1PV anticancer efficacy are also discussed.


Assuntos
Parvovirus H-1/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica , Vírus Oncolíticos/imunologia , Microambiente Tumoral/imunologia , Humanos
13.
Sci Rep ; 8(1): 12179, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111770

RESUMO

Immune responses are critical for defense against pathogens. However, prolonged viral infection can result in defective T cell immunity, leading to chronic viral infection. We studied immune activation in response to arenavirus infection during cholestasis using bile duct ligation (BDL). We monitored T cell responses, virus load and liver pathology markers after infection with lymphocytic choriomeningitis virus (LCMV). BDL mice failed to induce protective anti-viral immunity against LCMV and consequently exhibited chronic viral infection. BDL mice exhibited reduced anti-viral T cell immunity as well as reduced type 1 interferon production early after LCMV infection. Consistently, the presence of serum from BDL mice reduced the responsiveness of dendritic cell (DC) and T cell cultures when compared to Sham controls. Following fractionation and mass spectrometry analyses of sera, we identified several serum factors to be upregulated following BDL including bilirubin, bile acids, 78 kDa Glucose regulated protein (GRP78) and liver enzymes. Bilirubin and GRP78 were capable of inhibiting DC and T cell activation. In this work, we demonstrate that liver damage mediated by cholestasis results in defective immune induction following arenavirus infection.


Assuntos
Infecções por Arenaviridae/imunologia , Colestase/imunologia , Hepatopatias/imunologia , Fígado/imunologia , Animais , Infecções por Arenaviridae/patologia , Arenavirus/imunologia , Ductos Biliares/imunologia , Ductos Biliares/patologia , Linfócitos T CD4-Positivos/imunologia , Colestase/patologia , Células Dendríticas/imunologia , Chaperona BiP do Retículo Endoplasmático , Interferon Tipo I/imunologia , Fígado/patologia , Hepatopatias/patologia , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
14.
Sci Rep ; 7(1): 7938, 2017 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801579

RESUMO

The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4+. Cellular NH4+ uptake is accomplished mainly by the Na+,K+,2Cl- cotransporter. Here we show that hepatic clearance of NH4+ is impaired in TNFα deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4+, TNFα deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4+ load, virtually all TNFα deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFα treatment of wild type mice sensitized the animals to the toxic effects of an NH4+ load. The protection of TNFα-deficient mice against an NH4+ load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFα formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.


Assuntos
Hiperamonemia/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Fator de Necrose Tumoral alfa/deficiência , Amônia/toxicidade , Animais , Encéfalo/metabolismo , Hiperamonemia/metabolismo , Fígado/química , Camundongos , Camundongos Knockout , Membro 2 da Família 12 de Carreador de Soluto/genética , Fator de Necrose Tumoral alfa/genética , Regulação para Cima
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