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1.
PLoS One ; 13(3): e0194048, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29522531

RESUMO

Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin-producing pancreatic beta cells. While the role of adaptive immunity has been extensively studied, the role of innate immune responses and particularly of Toll- like Receptor (TLR) signaling in T1D remains poorly understood. Here we show that myeloid cell-specific MyD88 deficiency considerably protected mice from the development of streptozotocin (STZ)-induced diabetes. The protective effect of MyD88 deficiency correlated with increased expression of the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in pancreatic lymph nodes from STZ-treated mice and in bone marrow-derived dendritic cells (BMDC) stimulated with apoptotic cells. Mice with myeloid cell specific TIR-domain-containing adapter-inducing interferon-ß (TRIF) knockout showed a trend towards accelerated onset of STZ-induced diabetes, while TRIF deficiency resulted in reduced IDO expression in vivo and in vitro. Moreover, myeloid cell specific MyD88 deficiency delayed the onset of diabetes in Non-Obese Diabetic (NOD) mice, whereas TRIF deficiency had no effect. Taken together, these results identify MyD88 signaling in myeloid cells as a critical pathogenic factor in autoimmune diabetes, which is antagonized by TRIF-dependent responses. This differential function of MyD88 and TRIF depends at least in part on their opposite effects in regulating IDO expression in phagocytes exposed to apoptotic cells.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 1/etiologia , Células Mieloides/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Apoptose , Células Dendríticas/fisiologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Indução Enzimática , Feminino , Indolamina-Pirrol 2,3,-Dioxigenase/biossíntese , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interferon gama/biossíntese , Interferon gama/genética , Macrófagos Peritoneais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Fagocitose , Organismos Livres de Patógenos Específicos , Estreptozocina , Subpopulações de Linfócitos T/patologia
2.
Elife ; 72018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29337666

RESUMO

Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Linfócitos B/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/patologia , Orthomyxoviridae/imunologia , Linfócitos T/imunologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Animais , Adesão Celular , Proliferação de Células , Vacinas contra Influenza/administração & dosagem , Camundongos , Análise de Sobrevida
3.
Respir Res ; 18(1): 168, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28874189

RESUMO

Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFßRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EHITSN and SH3A-EITSN fragments. The EHITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EHITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology. As demonstrated in these studies, genetically modified ITSN-1s expression mouse models will be a valuable tool to further advance our understanding of pulmonary pathology and lead to novel targets for treating these conditions.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Animais , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Pneumopatias/etiologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo
4.
DNA Cell Biol ; 36(12): 1050-1061, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28945101

RESUMO

The present review provides a summary of recent evidence of sortilin expression, function, and regulation and its implications in lipid metabolism and development of lipid disorder diseases. As a member of the vacuolar protein sorting 10 protein (Vps10p) receptor family, sortilin mediates intracellular trafficking of diverse endogenous or exogenous protein substrates between the trans-Golgi network (TGN) and plasma membrane compartments. Recent studies reveal that sortilin regulates the expression of lipid genes, plasma lipid level, and the development of lipid disorder diseases. Sortilin promotes atherogenesis by regulating hepatic very low density lipoprotein (VLDL) secretion and plasma lipid level and subsequently macrophage lipid accumulation. Sortilin deficiency is caused by accelerated proteasome degradation under insulin resistance conditions and is thereby implicated in the hyperlipidemia of type 2 diabetes mellitus (T2DM). Sortilin facilitates hepatic cholesterol accumulation by inhibiting hepatic cholesterol catabolism, which promotes the development of nonalcoholic fatty liver disease (NAFLD). Sortilin plays an important role in lipid metabolism and represents a promising therapeutic target for lipid disorder diseases.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Transtornos do Metabolismo dos Lipídeos/etiologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Metabolismo dos Lipídeos , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/etiologia , Dislipidemias/metabolismo , Humanos , Metabolismo dos Lipídeos/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo
5.
Stem Cell Res Ther ; 8(1): 196, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28927462

RESUMO

BACKGROUND: Human induced pluripotent stem cells (iPSCs) have been verified as a powerful cell model for the study of pathogenesis in hereditary disease. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of PKD or non-PKD genes. The pathogenesis of ADPKD remains unexplored because of the lack of a true human cell model. METHODS: Six ADPKD patients and four healthy individuals were recruited as donors of somatic cells from a Chinese ADPKD family without mutations of the PKD genes but carrying SAMSN1 gene deletion. The ADPKD-iPSCs were generated from somatic cells and were induced into kidney-like cells (KLCs) by a novel three-step method involving cytokines and renal epithelium growth medium. Furthermore, we analyzed functional properties of these KLCs by water transportation and albumin absorption assays. RESULTS: We successfully generated iPSCs from ADPKD patients and differentiated them into KLCs that showed morphological and functional characteristics of human kidney cells. Further, we also found that ADPKD-iPSC-KLCs had a significantly higher rate of apoptosis and a significantly lower capacity for water transportation and albumin absorption compared to healthy sibling-derived differentiated KLCs. Furthermore, knockdown of SAMSN1 in control iPSCs may attenuate differentiation and/or function of KLCs. CONCLUSIONS: These data show that we have created the first iPSCs established from ADPKD patients without mutations in the PKD genes, and suggest that the deletion mutation of SAMSN1 might be involved in the differentiation and/or function of KLCs. ADPKD-iPSC-KLCs can be used as a versatile model system for the study of kidney disease.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Células Epiteliais/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Rim/metabolismo , Proteínas do Tecido Nervoso/genética , Rim Policístico Autossômico Dominante/genética , Receptores de Superfície Celular/genética , Canais de Cátion TRPP/genética , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Adolescente , Albuminas/metabolismo , Transporte Biológico , Diferenciação Celular , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Células Epiteliais/patologia , Feminino , Deleção de Genes , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Rim/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/deficiência , Linhagem , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Cultura Primária de Células , Receptores de Superfície Celular/deficiência , Canais de Cátion TRPP/metabolismo , Água/metabolismo
6.
J Immunol ; 199(7): 2460-2474, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28848065

RESUMO

Nucleic acids carrying pathogen-associated molecular patterns trigger innate immune responses and are used to activate host immunity. Although synthetic nucleic acids have been used for that purpose, they have shown limitations for in vivo and clinical applications. To address this issue, we tested a naturally occurring dsRNA extracted from rice bran (rb-dsRNA) and characterized it as a potent ligand of TLR3 and MDA5. In this study, intranasal administration of rb-dsRNA induced production of type I IFNs by alveolar macrophages and protected mice from morbidity and mortality resulting from respiratory virus infection, such as influenza A virus. This protection was completely absent in mice lacking both TRIF and MDA5, indicating the essential role of TLR3- and MDA5-dependent pathways. Interestingly, IFNAR1-deficient mice retained residual antiviral protection, which was abolished by pharmacological inhibition of caspase 1, but not IL-1ß signaling. In fact, rb-dsRNA activated caspase 1 via TRIF, resulting in the release of IL-1ß and LDH. In addition to the direct antiviral activity, rb-dsRNA modulated the immune cell population in the lungs by repopulating virus-depleted alveolar macrophages. Our data demonstrate that rb-dsRNA orchestrates IFN-dependent and -independent direct antiviral protection and that it is a potent immune stimulator modulating antiviral immunity in the lungs. These findings open doors to a range of precise immune-modulating studies and therapeutic options.


Assuntos
Antivirais/isolamento & purificação , Vírus da Influenza A/imunologia , Interferon Tipo I/imunologia , Infecções por Orthomyxoviridae/imunologia , Oryza/genética , RNA de Cadeia Dupla/imunologia , RNA de Cadeia Dupla/isolamento & purificação , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Antivirais/imunologia , Inibidores de Caspase/administração & dosagem , Imunidade Inata , Interferon Tipo I/biossíntese , Helicase IFIH1 Induzida por Interferon/química , Helicase IFIH1 Induzida por Interferon/deficiência , Helicase IFIH1 Induzida por Interferon/genética , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Ligantes , Pulmão/imunologia , Pulmão/virologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Camundongos , Infecções por Orthomyxoviridae/prevenção & controle , Oryza/química , Plantas/química , Plantas/genética , RNA de Cadeia Dupla/administração & dosagem , RNA de Cadeia Dupla/farmacologia , Receptor de Interferon alfa e beta/deficiência , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/química
7.
Am J Physiol Renal Physiol ; 313(1): F103-F115, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28356284

RESUMO

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4-/- or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-ß (TRIF)-/- mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Lipídeo A/análogos & derivados , Lipopolissacarídeos/toxicidade , Alça do Néfron/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Bicarbonatos/metabolismo , Citoproteção , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Técnicas In Vitro , Lipídeo A/farmacologia , Alça do Néfron/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Perfusão , Fosfatidilinositol 3-Quinase/antagonistas & inibidores , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Reabsorção Renal/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
8.
FEBS Lett ; 591(7): 1018-1028, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28236654

RESUMO

Sortilin 1 (Sort1) is a trafficking receptor that has been implicated in the regulation of plasma cholesterol in humans and mice. Here, we use metabolomics and hyperinsulinemic-euglycemic clamp approaches to obtain further understanding of the in vivo effects of Sort1 deletion on diet-induced obesity as well as on adipose lipid and glucose metabolism. Results show that Sort1 knockout (KO) does not affect Western diet-induced obesity nor adipose fatty acid and ceramide concentrations. Under the basal fasting state, chow-fed Sort1 KO mice have decreased adipose glycolytic metabolites, but Sort1 deletion does not affect insulin-stimulated tissue glucose uptake during the insulin clamp. These results suggest that Sort1 loss-of-function in vivo does not affect obesity development, but differentially modulates adipose glucose metabolism under fasting and insulin-stimulated states.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/deficiência , Tecido Adiposo/metabolismo , Glucose/metabolismo , Obesidade/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Metabolismo Basal , Ceramidas/metabolismo , Dieta Ocidental/efeitos adversos , Jejum , Ácidos Graxos/metabolismo , Técnica Clamp de Glucose , Glicólise , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/metabolismo , Insulina/administração & dosagem , Insulina/metabolismo , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/genética
9.
Am J Pathol ; 187(3): 528-542, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28068512

RESUMO

Murine models of pulmonary arterial hypertension (PAH) that recapitulate the plexiform and obliterative arteriopathy seen in PAH patients and help in defining the molecular mechanisms involved are missing. Herein, we investigated whether intersectin-1s (ITSN) deficiency and prolonged lung expression of an ITSN fragment with endothelial cell (EC) proliferative potential (EHITSN), present in the lungs of PAH animal models and human patients, induce formation of plexiform/obliterative lesions and defined the molecular mechanisms involved. ITSN-deficient mice (knockout/heterozygous and knockdown) were subjected to targeted lung delivery of EHITSN via liposomes for 20 days. Immunohistochemistry and histological and morphometric analyses revealed a twofold increase in proliferative ECs and a 1.35-fold increase in proliferative α-smooth muscle actin-positive cells in the lungs of ITSN-deficient mice, transduced with the EHITSN relative to wild-type littermates. Treated mice developed severe medial wall hypertrophy, intima proliferation, and various forms of obliterative and plexiform-like lesions in pulmonary arteries, similar to PAH patients. Hemodynamic measurements indicated modest increases in the right ventricular systolic pressure and right ventricle hypertrophy. Transcriptional and protein assays of lung tissue indicated p38MAPK-dependent activation of Elk-1 transcription factor and increased expression of c-Fos gene. This unique murine model of PAH-like plexiform/obliterative arteriopathy induced via a two-hit pathophysiological mechanism without hypoxia provides novel druggable targets to ameliorate and, perhaps, reverse the EC plexiform phenotype in severe human PAH.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Hipertensão Pulmonar/patologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Artéria Pulmonar/patologia , Remodelação Vascular , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Animais , Proliferação de Células , Colágeno/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão Pulmonar/fisiopatologia , Hipertrofia/patologia , Hipertrofia/fisiopatologia , Lipídeos/química , Pulmão/enzimologia , Pulmão/patologia , Camundongos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Artéria Pulmonar/fisiopatologia , RNA Interferente Pequeno/metabolismo , Sístole , Transdução Genética , Proteínas Elk-1 do Domínio ets/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
J Neurosci ; 37(2): 383-396, 2017 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-28077717

RESUMO

Synaptic vesicles fuse at morphological specializations in the presynaptic terminal termed active zones (AZs). Vesicle fusion can occur spontaneously or in response to an action potential. Following fusion, vesicles are retrieved and recycled within nerve terminals. It is still unclear whether vesicles that fuse spontaneously or following evoked release share similar recycling mechanisms. Genetic deletion of the SNARE-binding protein complexin dramatically increases spontaneous fusion, with the protein serving as the synaptic vesicle fusion clamp at Drosophila synapses. We examined synaptic vesicle recycling pathways at complexin null neuromuscular junctions, where spontaneous release is dramatically enhanced. We combined loading of the lipophilic dye FM1-43 with photoconversion, electron microscopy, and electrophysiology to monitor evoked and spontaneous recycling vesicle pools. We found that the total number of recycling vesicles was equal to those retrieved through spontaneous and evoked pools, suggesting that retrieval following fusion is partially segregated for spontaneous and evoked release. In addition, the kinetics of FM1-43 destaining and synaptic depression measured in the presence of the vesicle-refilling blocker bafilomycin indicated that spontaneous and evoked recycling pools partially intermix during the release process. Finally, FM1-43 photoconversion combined with electron microscopy analysis indicated that spontaneous recycling preferentially involves synaptic vesicles in the vicinity of AZs, whereas vesicles recycled following evoked release involve a larger intraterminal pool. Together, these results suggest that spontaneous and evoked vesicles use separable recycling pathways and then partially intermix during subsequent rounds of fusion. SIGNIFICANCE STATEMENT: Neurotransmitter release involves fusion of synaptic vesicles with the plasma membrane in response to an action potential, or spontaneously in the absence of stimulation. Upon fusion, vesicles are retrieved and recycled, and it is unclear whether recycling pathways for evoked and spontaneous vesicles are segregated after fusion. We addressed this question by taking advantage of preparations lacking the synaptic protein complexin, which have elevated spontaneous release that enables reliable tracking of the spontaneous recycling pool. Our results suggest that spontaneous and evoked recycling pathways are segregated during the retrieval process but can partially intermix during stimulation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas de Drosophila/deficiência , Exocitose/fisiologia , Mutação/fisiologia , Proteínas do Tecido Nervoso/deficiência , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Feminino , Masculino , Proteínas do Tecido Nervoso/genética , Vesículas Sinápticas/genética , Vesículas Sinápticas/ultraestrutura
11.
Cell Death Differ ; 24(3): 385-396, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27834952

RESUMO

PolyI:C, a synthetic double-stranded RNA analog, acts as an immune-enhancing adjuvant that regresses tumors in cytotoxic T lymphocyte (CTL)-dependent and CTL-independent manner, the latter of which remains largely unknown. Tumors contain CD11b+Ly6G+ cells, known as granulocytic myeloid-derived suppressor cells (G-MDSCs) or tumor-associated neutrophils (TANs) that play a critical role in tumor progression and development. Here, we demonstrate that CD11b+Ly6G+ cells respond to polyI:C and exhibit tumoricidal activity in an EL4 tumor implant model. PolyI:C-induced inhibition of tumor growth was attributed to caspase-8/3 cascade activation in tumor cells that occurred independently of CD8α+/CD103+ dendritic cells (DCs) and CTLs. CD11b+Ly6G+ cells was essential for the antitumor effect because depletion of CD11b+Ly6G+ cells totally abrogated tumor regression and caspase activation after polyI:C treatment. CD11b+Ly6G+ cells that had been activated with polyI:C showed cytotoxicity and inhibited tumor growth through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS). These responses were abolished in either Toll/interleukin-1 receptor domain-containing adaptor molecule-1 (TICAM-1)-/- or interferon (IFN)-αß receptor 1 (IFNAR1)-/- mice. Thus, our results suggest that polyI:C activates the TLR3/TICAM-1 and IFNAR signaling pathways in CD11b+Ly6G+ cells in tumors, thereby eliciting their antitumor activity, independent of those in CD8α+/CD103+ DCs that prime CTLs.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , RNA de Cadeia Dupla/metabolismo , Linfócitos T Citotóxicos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Antígenos Ly/imunologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Células Mieloides/metabolismo , Poli I-C/farmacologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Transdução de Sinais/efeitos dos fármacos , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/efeitos dos fármacos
12.
Am J Pathol ; 187(1): 122-133, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27842214

RESUMO

Sortilin, a member of the vacuolar protein sorting 10 domain receptor family, traffics newly synthesized proteins from the trans-Golgi network to secretory pathways, endosomes, and cell surface. Sortilin-trafficked molecules, including IL-6 and acid sphingomyelinase (aSMase), mediate cholangiocyte proliferation and liver inflammation, hepatic stellate cell activation, hepatocyte apoptosis, and fibrosis. Based on these sortilin-regulated functions, we investigated its role in biliary damage leading to hepatocellular injury and fibrosis. Sortilin-/- mice displayed impaired inflammation and ductular reaction 3 days after bile duct ligation (BDL), as demonstrated by reduced cholangiocyte proliferation and activation and reduced serum IL-6. Interestingly, liver fibrosis was reduced in Sortilin-/- mice after both BDL and carbon tetrachloride treatment, in line with attenuated in vitro activation of Sortilin-/- hepatic stellate cells. Sortilin-/- hepatic aSMase activity was reduced in the BDL and carbon tetrachloride models and accompanied by reduced in vivo hepatocyte apoptosis. In addition, wild type (WT), but not Sortilin-/- hepatocytes, had increased aSMase-dependent susceptibility to bile acid-induced apoptosis in vitro. Mechanistically, short-term IL-6 neutralization in bile duct-ligated WT mice decreased hepatic inflammation and reactive cholangiocyte-derived cytokines and chemokines, without affecting fibrosis, whereas pharmacological inhibition of aSMase activity was not sufficient to attenuate hepatic fibrosis. Only combined IL-6 and aSMase inhibition significantly reduced fibrosis in bile duct-ligated WT mice. We conclude that sortilin regulates cholestatic liver damage and fibrosis via effects on both aSMase activity and serum IL-6.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/deficiência , Apoptose , Ductos Biliares/patologia , Colestase/complicações , Hepatócitos/patologia , Cirrose Hepática/patologia , Fígado/lesões , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Proliferação de Células , Quimiocinas/metabolismo , Colestase/patologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatócitos/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Camundongos Endogâmicos C57BL , Testes de Neutralização , Fenótipo , Esfingomielina Fosfodiesterase/metabolismo
13.
Nature ; 540(7631): 129-133, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27819682

RESUMO

Receptor-interacting protein kinase 1 (RIPK1) promotes cell survival-mice lacking RIPK1 die perinatally, exhibiting aberrant caspase-8-dependent apoptosis and mixed lineage kinase-like (MLKL)-dependent necroptosis. However, mice expressing catalytically inactive RIPK1 are viable, and an ill-defined pro-survival function for the RIPK1 scaffold has therefore been proposed. Here we show that the RIP homotypic interaction motif (RHIM) in RIPK1 prevents the RHIM-containing adaptor protein ZBP1 (Z-DNA binding protein 1; also known as DAI or DLM1) from activating RIPK3 upstream of MLKL. Ripk1RHIM/RHIM mice that expressed mutant RIPK1 with critical RHIM residues IQIG mutated to AAAA died around birth and exhibited RIPK3 autophosphorylation on Thr231 and Ser232, which is a hallmark of necroptosis, in the skin and thymus. Blocking necroptosis with catalytically inactive RIPK3(D161N), RHIM mutant RIPK3, RIPK3 deficiency, or MLKL deficiency prevented lethality in Ripk1RHIM/RHIM mice. Loss of ZBP1, which engages RIPK3 in response to certain viruses but previously had no defined role in development, also prevented perinatal lethality in Ripk1RHIM/RHIM mice. Consistent with the RHIM of RIPK1 functioning as a brake that prevents ZBP1 from engaging the RIPK3 RHIM, ZBP1 interacted with RIPK3 in Ripk1RHIM/RHIMMlkl-/- macrophages, but not in wild-type, Mlkl-/- or Ripk1RHIM/RHIMRipk3RHIM/RHIM macrophages. Collectively, these findings indicate that the RHIM of RIPK1 is critical for preventing ZBP1/RIPK3/MLKL-dependent necroptosis during development.


Assuntos
Apoptose , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Glicoproteínas/antagonistas & inibidores , Glicoproteínas/metabolismo , Necrose , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Motivos de Aminoácidos , Animais , Animais Recém-Nascidos , Caspase 8/genética , Caspase 8/metabolismo , Embrião de Mamíferos/citologia , Feminino , Glicoproteínas/química , Glicoproteínas/deficiência , Macrófagos/metabolismo , Masculino , Camundongos , Mutação , Fosforilação , Ligação Proteica , Proteínas Quinases/deficiência , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/química , Proteína Serina-Treonina Quinases de Interação com Receptores/deficiência , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Fator de Necrose Tumoral alfa/farmacologia
14.
Sci Rep ; 6: 35947, 2016 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-27779214

RESUMO

Disabled-2 (Dab2) is a widely expressed clathrin binding endocytic adaptor protein and known for the endocytosis of the low-density lipoprotein (LDL) family receptors. Dab2 also modulates endosomal Ras/MAPK (Erk1/2) activity by regulating the disassembly of Grb2/Sos1 complexes associated with clathrin-coated vesicles. We found that the most prominent phenotype of Dab2 knockout mice was their striking lean body composition under a high fat and high caloric diet, although the weight of the mutant mice was indistinguishable from wild-type littermates on a regular chow. The remarkable difference in resistance to high caloric diet-induced weight gain of the dab2-deleted mice was presented only in juvenile but not in mature mice. Investigation using Dab2-deficient embryonic fibroblasts and mesenchymal stromal cells indicated that Dab2 promoted adipogenic differentiation by modulation of MAPK (Erk1/2) activity, which otherwise suppresses adipogenesis through the phosphorylation of PPARγ. The results suggest that Dab2 is required for the excessive calorie-induced differentiation of an adipocyte progenitor cell population that is present in juvenile but depleted in mature animals. The finding provides evidence for a limited pre-adipocyte population in juvenile mammals and the requirement of Dab2 in the regulation of Ras/MAPK signal in the commitment of the precursor cells to adipose tissues.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Adipócitos/fisiologia , Diferenciação Celular , Fibroblastos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Animais , Peso Corporal , Células Cultivadas , Dieta Hiperlipídica , Regulação da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Camundongos Knockout
15.
Mol Cancer ; 15(1): 59, 2016 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-27629044

RESUMO

BACKGROUND: The mechanisms involved in lung cancer (LC) progression are poorly understood making discovery of successful therapies difficult. Adaptor proteins play a crucial role in cancer as they link cell surface receptors to specific intracellular pathways. Intersectin-1s (ITSN-1s) is an important multidomain adaptor protein implicated in the pathophysiology of numerous pulmonary diseases. To date, the role of ITSN-1s in LC has not been studied. METHODS: Human LC cells, human LC tissue and A549 LC cells stable transfected with myc-ITSN-1s construct (A549 + ITSN-1s) were used in correlation with biochemical, molecular biology and morphological studies. In addition scratch assay with time lapse microscopy and in vivo xenograft tumor and mouse metastasis assays were performed. RESULTS: ITSN-1s, a prevalent protein of lung tissue, is significantly downregulated in human LC cells and LC tissue. Restoring ITSN-1s protein level decreases LC cell proliferation and clonogenic potential. In vivo studies indicate that immunodeficient mice injected with A549 + ITSN-1s cells develop less and smaller metastatic tumors compared to mice injected with A549 cells. Our studies also show that restoring ITSN-1s protein level increases the interaction between Cbl E3 ubiquitin ligase and Eps8 resulting in enhanced ubiquitination of the Eps8 oncoprotein. Subsequently, downstream unproductive assembly of the Eps8-mSos1 complex leads to impaired activation of the small GTPase Rac1. Impaired Rac1 activation mediated by ITSN-1s reorganizes the cytoskeleton (increased thick actin bundles and focal adhesion (FA) complexes as well as collapse of the vimentin filament network) in favor of decreased LC cell migration and metastasis. CONCLUSION: ITSN-1s induced Eps8 ubiquitination and impaired Eps8-mSos1 complex formation, leading to impaired activation of Rac1, is a novel signaling mechanism crucial for abolishing the progression and metastatic potential of LC cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteína SOS1/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-cbl/genética , Proteína SOS1/genética , Imagem com Lapso de Tempo , Ubiquitinação , Proteínas rac1 de Ligação ao GTP/genética
16.
J Leukoc Biol ; 100(5): 1011-1025, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27531927

RESUMO

Skeletal muscle regeneration requires coordination between dynamic cellular populations and tissue microenvironments. Macrophages, recruited via CCR2, are essential for regeneration; however, the contribution of macrophages and the role of CCR2 on nonhematopoietic cells has not been defined. In addition, aging and sex interactions in regeneration and sarcopenia are unclear. Muscle regeneration was measured in young (3-6 mo), middle (11-15 mo), old (24-32 mo) male and female CCR2-/- mice. Whereas age-related muscle atrophy/sarcopenia was present, regenerated myofiber cross-sectional area (CSA) in CCR2-/- mice was comparably impaired across all ages and sexes, with increased adipocyte area compared with wild-type (WT) mice. CCR2-/- mice myofibers achieved approximately one third of baseline CSA even 84 d after injury. Regenerated CSA and clearance of necrotic tissue were dependent on bone marrow-derived cellular expression of CCR2. Myogenic progenitor cells isolated from WT and CCR2-/- mice exhibited comparable proliferation and differentiation capacity. The most striking cellular anomaly in injured muscle of CCR2-/- mice was markedly decreased macrophages, with a predominance of Ly6C- anti-inflammatory monocytes/macrophages. Ablation of proinflammatory TLR signaling did not affect muscle regeneration or resolution of necrosis. Of interest, many proinflammatory, proangiogenic, and chemotactic cytokines were markedly elevated in injured muscle of CCR2-/- relative to WT mice despite impairments in macrophage recruitment. Collectively, these results suggest that CCR2 on bone marrow-derived cells, likely macrophages, were essential to muscle regeneration independent of TLR signaling, aging, and sex. Decreased proinflammatory monocytes/macrophages actually promoted a proinflammatory microenvironment, which suggests that inflammaging was present in young CCR2-/- mice.


Assuntos
Macrófagos/fisiologia , Músculo Esquelético/fisiologia , Miosite/fisiopatologia , Receptores CCR2/deficiência , Regeneração/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Envelhecimento/imunologia , Animais , Peso Corporal , Ciclo Celular , Divisão Celular , Citocinas/sangue , Feminino , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Monócitos/fisiologia , Desenvolvimento Muscular , Músculo Esquelético/lesões , Fator 88 de Diferenciação Mieloide/deficiência , Mioblastos/patologia , Necrose , Quimera por Radiação , Receptores CCR2/fisiologia , Sarcopenia/fisiopatologia , Organismos Livres de Patógenos Específicos
17.
N Engl J Med ; 375(5): 411-421, 2016 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-27518660

RESUMO

BACKGROUND: The Amish and Hutterites are U.S. agricultural populations whose lifestyles are remarkably similar in many respects but whose farming practices, in particular, are distinct; the former follow traditional farming practices whereas the latter use industrialized farming practices. The populations also show striking disparities in the prevalence of asthma, and little is known about the immune responses underlying these disparities. METHODS: We studied environmental exposures, genetic ancestry, and immune profiles among 60 Amish and Hutterite children, measuring levels of allergens and endotoxins and assessing the microbiome composition of indoor dust samples. Whole blood was collected to measure serum IgE levels, cytokine responses, and gene expression, and peripheral-blood leukocytes were phenotyped with flow cytometry. The effects of dust extracts obtained from Amish and Hutterite homes on immune and airway responses were assessed in a murine model of experimental allergic asthma. RESULTS: Despite the similar genetic ancestries and lifestyles of Amish and Hutterite children, the prevalence of asthma and allergic sensitization was 4 and 6 times as low in the Amish, whereas median endotoxin levels in Amish house dust was 6.8 times as high. Differences in microbial composition were also observed in dust samples from Amish and Hutterite homes. Profound differences in the proportions, phenotypes, and functions of innate immune cells were also found between the two groups of children. In a mouse model of experimental allergic asthma, the intranasal instillation of dust extracts from Amish but not Hutterite homes significantly inhibited airway hyperreactivity and eosinophilia. These protective effects were abrogated in mice that were deficient in MyD88 and Trif, molecules that are critical in innate immune signaling. CONCLUSIONS: The results of our studies in humans and mice indicate that the Amish environment provides protection against asthma by engaging and shaping the innate immune response. (Funded by the National Institutes of Health and others.).


Assuntos
Agricultura , Asma/imunologia , Exposição Ambiental , Imunidade Inata , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Adolescente , Animais , Asma/epidemiologia , Criança , Cristianismo , Estudos Transversais , Citocinas/sangue , Modelos Animais de Doenças , Poeira/imunologia , Feminino , Expressão Gênica , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Imunoglobulina E/sangue , Contagem de Leucócitos , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Animais , Fator 88 de Diferenciação Mieloide/deficiência , Prevalência
18.
Sci Rep ; 6: 29332, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27389464

RESUMO

Sorting of luminal and membrane proteins into phagosomes is critical for the immune function of this organelle. However, little is known about the mechanisms that contribute to the spatiotemporal regulation of this process. Here, we investigated the role of the proneurotrophin receptor sortilin during phagosome maturation and mycobacterial killing. We show that this receptor is acquired by mycobacteria-containing phagosomes via interactions with the adaptor proteins AP-1 and GGAs. Interestingly, the phagosomal association of sortilin is critical for the delivery of acid sphingomyelinase (ASMase) and required for efficient phagosome maturation. Macrophages from Sort1(-/-) mice are less efficient in restricting the growth of Mycobacterium bovis BCG and M. tuberculosis. In vivo, Sort1(-/-) mice showed a substantial increase in cellular infiltration of neutrophils in their lungs and higher bacterial burden after infection with M. tuberculosis. Altogether, sortilin defines a pathway required for optimal intracellular mycobacteria control and lung inflammation in vivo.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Fagossomos/metabolismo , Fagossomos/microbiologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Animais , Carga Bacteriana , Modelos Animais de Doenças , Pulmão/microbiologia , Camundongos , Camundongos Knockout , Viabilidade Microbiana , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia
19.
J Leukoc Biol ; 100(6): 1311-1322, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27354411

RESUMO

Treatment with the TLR4 agonist MPLA augments innate resistance to common bacterial pathogens. However, the cellular and molecular mechanisms by which MPLA augments innate immunocyte functions are not well characterized. This study examined the importance of MyD88- and TRIF-dependent signaling for leukocyte mobilization, recruitment, and activation following administration of MPLA. MPLA potently induced MyD88- and TRIF-dependent signaling. A single injection of MPLA caused rapid mobilization and recruitment of neutrophils, a response that was largely mediated by the chemokines CXCL1 and -2 and the hemopoietic factor G-CSF. Rapid neutrophil recruitment and chemokine production were regulated by both pathways although the MyD88-dependent pathway showed some predominance. In further studies, multiple injections of MPLA potently induced mobilization and recruitment of neutrophils and monocytes. Neutrophil recruitment after multiple injections of MPLA was reliant on MyD88-dependent signaling, but effective monocyte recruitment required activation of both pathways. MPLA treatment induced expansion of myeloid progenitors in bone marrow and upregulation of CD11b and shedding of L-selectin by neutrophils, all of which were attenuated in MyD88- and TRIF-deficient mice. These results show that MPLA-induced neutrophil and monocyte recruitment, expansion of bone marrow progenitors and augmentation of neutrophil adhesion molecule expression are regulated by both the MyD88- and TRIF-dependent pathways.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Imunidade Inata , Lipídeo A/análogos & derivados , Monócitos/imunologia , Fator 88 de Diferenciação Mieloide/fisiologia , Neutrófilos/imunologia , Receptor 4 Toll-Like/agonistas , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Animais , Antígeno CD11b/biossíntese , Antígeno CD11b/genética , Quimiocina CXCL1/fisiologia , Quimiocina CXCL2/fisiologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/fisiologia , Selectina L/metabolismo , Lipídeo A/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/deficiência , Mielopoese/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Receptores de Interleucina-8B/fisiologia , Transdução de Sinais , Receptor 4 Toll-Like/fisiologia
20.
Stem Cell Reports ; 6(6): 940-956, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27264973

RESUMO

Toll-like receptor 4 (TLR4) plays a central role in host responses to bacterial infection, but the precise mechanism(s) by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC) functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/imunologia , Células-Tronco Hematopoéticas/patologia , Células Mieloides/patologia , Fator 88 de Diferenciação Mieloide/imunologia , Sepse/imunologia , Proteínas Adaptadoras de Transporte Vesicular/deficiência , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/imunologia , Ciclo Celular , Modelos Animais de Doenças , Regulação da Expressão Gênica , Células-Tronco Hematopoéticas/imunologia , Lipopolissacarídeos , Camundongos , Camundongos Knockout , Células Mieloides/imunologia , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Sepse/genética , Sepse/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Transativadores/genética , Transativadores/imunologia , Transcrição Genética
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