Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 185
Filtrar
2.
Nihon Shokakibyo Gakkai Zasshi ; 118(9): 868-873, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34511554

RESUMO

A 62-year-old man presented to our hospital with difficulty in swallowing. Physical examination and subsequent diagnostic tests identified hypopharyngeal and esophageal carcinoma with tracheal invasion. The patient underwent gastric fistula placement, radiotherapy, and chemotherapy. Palliative care was initiated after recurrence. The patient was later hospitalized for neck pain, and during a routine exchange of the gastric fistula, two large bezoars were found. The enteral nutrient gel was discontinued, cola was administered, and the bezoars gradually reduced. He continued to receive home care, and later when he was hospitalized for mediastinal abscess, no bezoars were identified. This case highlights the possibility of bezoar formation as a rare complication of enteral nutrition gel administration.


Assuntos
Bezoares , Neoplasias Esofágicas , Fístula Gástrica , Bezoares/diagnóstico por imagem , Bezoares/etiologia , Neoplasias Esofágicas/tratamento farmacológico , Fístula Gástrica/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Nutrientes
3.
Front Immunol ; 12: 669629, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34305899

RESUMO

Background and aims: Group 2 innate lymphoid cells (ILC2s) have been implicated in the regulation of metabolic homeostasis in mice. Methods: In this study, the role of ILC2s in white adipose tissue (WAT) was investigated using ST2, an IL-33 receptor that is expressed on ILC2 knockout mice. Results: The deficiency of ST2 decreased ILC2s in WAT, whereas ex-ILC2, which acquired group 1 innate lymphoid cell (ILC1)-like traits, was increased. This led to significant metabolic disorders such as visceral fat obesity, decreased browning in WAT, reduction of energy metabolism, and impaired glucose tolerance, compared to wild type (WT) mice. Those metabolic abnormalities of ST2-knockout (ST2KO) mice were not ameliorated by IL-33 administration, but impaired glucose tolerance and visceral fat obesity were significantly improved by transplantation of ILCs from the bone marrow of WT mice. The relative expression of Cd36 in WAT increased due to the deficiency of ST2, and the storage of saturated fatty acids in WAT of ST2KO mice was significantly higher than that of WT mice. Moreover, saturated fatty acids aggravated the chronic inflammation in adipocytes, promoted the differentiation of M1-like macrophages, and inhibited that of M2-like macrophages. Conclusions: Our results indicated that ILC2 regulates diet-induced obesity and chronic inflammation through the regulation of saturated fatty acid absorption in visceral adipose tissue.


Assuntos
Glicemia/metabolismo , Ácidos Graxos/metabolismo , Intolerância à Glucose/metabolismo , Imunidade Inata , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Linfócitos/metabolismo , Absorção Fisiológica , Transferência Adotiva , Animais , Glicemia/efeitos dos fármacos , Antígenos CD36/metabolismo , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/genética , Intolerância à Glucose/imunologia , Homeostase , Imunidade Inata/efeitos dos fármacos , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/farmacologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/imunologia , Obesidade/metabolismo , Células RAW 264.7
4.
Sci Rep ; 11(1): 11816, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083649

RESUMO

Molecular mimicry is one of the main processes for producing autoantibodies during infections. Although some autoantibodies are associated with autoimmune diseases, the functions of many autoantibodies remain unknown. Previously, we reported that S16, a mouse (BALB/c) monoclonal antibody against the hemagglutinin-esterase fusion glycoprotein of influenza C virus, recognizes host proteins in some species of animals, but we could not succeed in identifying the proteins. In the present study, we found that S16 cross-reacted with acetyl-CoA acyltransferase 2 (ACAA2), which is expressed in the livers of BALB/c mice. ACAA2 was released into the serum after acetaminophen (APAP) administration, and its serum level correlated with serum alanine aminotransferase (ALT) activity. Furthermore, we observed that S16 injected into mice with APAP-induced hepatic injury prompted the formation of an immune complex between S16 and ACAA2 in the serum. The levels of serum ALT (p < 0.01) and necrotic areas in the liver (p < 0.01) were reduced in the S16-injected mice. These results suggest that S16 may have a mitigation function in response to APAP-induced hepatotoxicity. This study shows the therapeutic function of an autoantibody and suggests that an antibody against extracellular ACAA2 might be a candidate for treating APAP-induced hepatic injury.


Assuntos
Acetaminofen/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/etiologia , Influenzavirus C/imunologia , Acetil-CoA C-Aciltransferase , Animais , Especificidade de Anticorpos , Complexo Antígeno-Anticorpo , Doença Hepática Crônica Induzida por Substâncias e Drogas/diagnóstico , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Espectrometria de Massas , Camundongos , Ligação Proteica , Transporte Proteico
5.
Proc Natl Acad Sci U S A ; 118(26)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34168078

RESUMO

Chronic obstructive pulmonary disease (COPD/emphysema) is a life-threatening disorder and there are few effective therapies. Cigarette smoke-induced oxidative stress, airway inflammation, and apoptosis of lung cells have been reported to be involved in the pathogenesis of COPD/emphysema and lead to alveolar septal destruction. Here we show that the expression level of FCH and double SH3 domains 1 (FCHSD1) was drastically increased in mice in response to elastase instillation, an experimental model of COPD. FCHSD1 is a member of the F-BAR family with two SH3 domains. We found that Fchsd1 knockout (Fchsd1 -/-) mice were protected against airspace enlargement induced by elastase. Elastase-instilled lungs of Fchsd1 -/- mice showed reduced inflammation and apoptosis compared with WT mice. We also found that elastase-induced reduction of Sirtuin 1 (SIRT1) levels, a histone deacetylase reported to protect against emphysema, was attenuated in the lungs of Fchsd1 -/- mice. Furthermore, FCHSD1 deficiency enhanced nuclear translocation of nuclear factor-like 2 (NRF2), a redox-sensitive transcription factor, following H2O2 stimulation. Conversely, Fchsd1 overexpression inhibited NRF2 nuclear translocation and increased the reduction of SIRT1 levels. Notably, FCHSD1 interacted with NRF2 and SNX9. Our results show that FCHSD1 forms a multicomplex with NRF2 and SNX9 in the cytosol that prevents NRF2 from translocating to the nucleus. We propose that FCHSD1 promotes initiation of emphysema development by inhibiting nuclear translocation of NRF2, which leads to down-regulation of SIRT1.

6.
Front Immunol ; 12: 663115, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34163472

RESUMO

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.


Assuntos
Plasticidade Celular/imunologia , Imunomodulação , Monócitos/imunologia , Monócitos/metabolismo , Neoplasias/etiologia , Neoplasias/patologia , Animais , Antígenos Ly/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Imunomodulação/genética , Imunofenotipagem , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias/metabolismo , Neoplasias/terapia , Receptores CXCR4/metabolismo
7.
Respir Res ; 22(1): 150, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33992109

RESUMO

BACKGROUND: IL-33, which is known to induce type 2 immune responses via group 2 innate lymphoid cells, has been reported to contribute to neutrophilic airway inflammation in chronic obstructive pulmonary disease. However, its role in the pathogenesis of emphysema remains unclear. METHODS: We determined the role of interleukin (IL)-33 in the development of emphysema using porcine pancreas elastase (PPE) and cigarette smoke extract (CSE) in mice. First, IL-33-/- mice and wild-type (WT) mice were given PPE intratracheally. The numbers of inflammatory cells, and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates, were analyzed; quantitative morphometry of lung sections was also performed. Second, mice received CSE by intratracheal instillation. Quantitative morphometry of lung sections was then performed again. RESULTS: Intratracheal instillation of PPE induced emphysematous changes and increased IL-33 levels in the lungs. Compared to WT mice, IL-33-/- mice showed significantly greater PPE-induced emphysematous changes. No differences were observed between IL-33-/- and WT mice in the numbers of macrophages or neutrophils in BAL fluid. The levels of hepatocyte growth factor were lower in the BAL fluid of PPE-treated IL-33-/- mice than WT mice. IL-33-/- mice also showed significantly greater emphysematous changes in the lungs, compared to WT mice, following intratracheal instillation of CSE. CONCLUSION: These observations suggest that loss of IL-33 promotes the development of emphysema and may be potentially harmful to patients with COPD.

8.
Diabetes ; 70(8): 1738-1753, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33975909

RESUMO

The current understanding of the molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas overexpressed TRIB3 and investigated the role of TRIB3 in diabetic retinal pathobiology in mice. We discovered that TRIB3 controlled major molecular events in early diabetic retinas via HIF1α-mediated regulation of retinal glucose flux, reprogramming cellular metabolism, and governing of inflammatory gene expression. These early molecular events further defined the development of neurovascular deficit observed in mice with diabetic retinopathy. TRIB3 ablation in the streptozotocin-induced mouse model led to significant retinal ganglion cell survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation. Under hypoxic conditions, TRIB3 contributed to advanced proliferative stages by significant upregulation of GFAP and VEGF expression, thus controlling gliosis and aberrant vascularization in oxygen-induced retinopathy mouse retinas. Overall, our data reveal that TRIB3 is a master regulator of diabetic retinal pathophysiology that may accelerate the onset and progression of diabetic retinopathy to proliferative stages in humans and present TRIB3 as a potentially novel therapeutic target for diabetic retinopathy.


Assuntos
Proteínas de Ciclo Celular/genética , Retinopatia Diabética/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/genética , Retina/metabolismo , Animais , Capilares/metabolismo , Capilares/patologia , Proteínas de Ciclo Celular/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Progressão da Doença , Humanos , Camundongos , Pericitos/metabolismo , Pericitos/patologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Repressoras/metabolismo , Retina/patologia
9.
Biol Pharm Bull ; 44(2): 275-278, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33518681

RESUMO

α-Defensin 5 has a particularly broad antibacterial spectrum; it eliminates pathogenic microorganisms and regulates intestinal flora. Although Caco-2 cells are similar to small intestinal cells, it is unclear whether they secrete α-defensin 5. Therefore, we investigated whether Caco-2 cells secrete α-defensin 5 and determined the secretion mechanism using cells from three cell banks (ATCC, DSMZ, and RIKEN). The Caco-2 cell proliferation rate increased with the number of culture days, irrespective of cell bank origin. On the other hand, the alkaline phosphatase activity, which affects cell differentiation and the mRNA levels of several cytokines, such as interleukin 8 (IL-8), IL-6, IL-1ß, tumor necrosis factor-α (TNF-α), and IL-2, in the Caco-2 cells fluctuated with the number of culture days, and differed for each cell bank. α-Defensin 5 secretion was detected in all three cell bank Caco-2 cells; particularly, the ATCC Caco-2 cells grew linearly depending on the cell culture day as well as the levels of IL-8 and TNF-α mRNA. This suggested that α-defensin 5 secretion in the ATCC Caco-2 cells was associated with fluctuations in the mRNA levels of various cytokines, such as IL-8 and TNF-α. In conclusion, Caco-2 cells may be a simple model for screening health food components and drugs that affect α-defensin 5 secretion.


Assuntos
Células CACO-2/metabolismo , alfa-Defensinas/metabolismo , Bancos de Espécimes Biológicos , Proliferação de Células , Citocinas/análise , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Estudos de Viabilidade , Humanos , Reprodutibilidade dos Testes , alfa-Defensinas/análise
10.
Exp Neurol ; 335: 113496, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038415

RESUMO

Mutations in the genes TARDBP (encoding the TDP-43 protein) and TBK1 can cause familial ALS. Neuronal cytoplasmatic accumulations of the misfolded, hyperphosphorylated RNA-binding protein TDP-43 are the pathological hallmark of most ALS cases and have been suggested to be a key aspect of ALS pathogenesis. Pharmacological induction of autophagy has been shown to reduce mutant TDP-43 aggregates and alleviate motor deficits in mice. TBK1 is exemplary for several other ALS genes that regulate autophagy. Consequently, we employed double mutant mice with both a heterozygous Tbk1 deletion and transgenic expression of human TDP-43G298S to test the hypothesis that impaired autophagy reduces intracellular clearance of an aggregation-prone protein and enhances toxicity of mutant TDP-43. The heterozygous deletion of Tbk1 did not change expression or cellular distribution of TDP-43 protein, motor neuron loss or reactive gliosis in the spinal cord of double-mutant mice at the age of 19 months. However, it aggravated muscle denervation and, albeit to a small and variable degree, motor dysfunction in TDP-43G298S transgenic mice, as similarly observed in the SOD1G93A transgenic mouse model for ALS before. Conclusively, our findings suggest that TBK1 mutations can affect the neuromuscular synapse.


Assuntos
Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Proteínas de Ligação a DNA/genética , Junção Neuromuscular/patologia , Proteínas Serina-Treonina Quinases/genética , Animais , Deleção de Genes , Gliose/genética , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios Motores/patologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Denervação Muscular , Mutação , Medula Espinal/patologia
11.
Dig Dis ; 39(3): 234-242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32759604

RESUMO

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/µL with an increased platelet count of ≥2 × 104/µL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/µL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.


Assuntos
Autoanticorpos/biossíntese , Linfócitos B/imunologia , Cinamatos/uso terapêutico , Hepatopatias/complicações , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/imunologia , Tiazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/imunologia , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Plaquetas/patologia , Cinamatos/administração & dosagem , Feminino , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Tamanho do Órgão , Contagem de Plaquetas , Estudos Prospectivos , Baço/patologia , Tiazóis/administração & dosagem , Trombocitopenia/sangue , Trombocitopenia/complicações
12.
Nat Commun ; 11(1): 5061, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033262

RESUMO

The interplay between the Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and transcriptional/epigenetic co-regulators in somatic cell reprogramming is incompletely understood. Here, we demonstrate that the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3 plays conflicting roles in mouse reprogramming. On one side, JMJD3 induces the pro-senescence factor Ink4a and degrades the pluripotency regulator PHF20 in a reprogramming factor-independent manner. On the other side, JMJD3 is specifically recruited by KLF4 to reduce H3K27me3 at both enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL and ultimately transcriptional elongation. This competition of forces can be shifted towards improved reprogramming by using early passage fibroblasts or boosting JMJD3's catalytic activity with vitamin C. Our work, thus, establishes a multifaceted role for JMJD3, placing it as a key partner of KLF4 and a scaffold that assists chromatin interactions and activates gene transcription.


Assuntos
Reprogramação Celular , Histona Desmetilases com o Domínio Jumonji/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Animais , Catálise , Proliferação de Células , Senescência Celular , Desmetilação , Elementos Facilitadores Genéticos/genética , Células Epiteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Histonas/metabolismo , Lisina/metabolismo , Camundongos , Modelos Biológicos , Regiões Promotoras Genéticas , Ativação Transcricional/genética
13.
Brain Commun ; 2(2): fcaa133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005894

RESUMO

Loss-of-function mutations in TANK-binding kinase 1 cause genetic amyotrophic lateral sclerosis and frontotemporal dementia. Consistent with incomplete penetrance in humans, haploinsufficiency of TANK-binding kinase 1 did not cause motor symptoms in mice up to 7 months of age in a previous study. Ageing is the strongest risk factor for neurodegenerative diseases. Hypothesizing that age-dependent processes together with haploinsufficiency of TANK-binding kinase 1 could create a double hit situation that may trigger neurodegeneration, we examined mice with hemizygous deletion of Tbk1 (Tbk1 +/- mice) and wild-type siblings up to 22 months. Compared to 4-month old mice, aged, 22-month old mice showed glial activation, deposition of motoneuronal p62 aggregates, muscular denervation and profound transcriptomic alterations in a set of 800 immune-related genes upon ageing. However, we did not observe differences regarding these measures between aged Tbk1 +/- and wild-type siblings. High age did also not precipitate TAR DNA-binding protein 43 aggregation, neurodegeneration or a neurological phenotype in Tbk1+/ - mice. In young Tbk1+/ - mice, however, we found the CNS immune gene expression pattern shifted towards the age-dependent immune system dysregulation observed in old mice. Conclusively, ageing is not sufficient to precipitate an amyotrophic lateral sclerosis or frontotemporal dementia phenotype or spinal or cortical neurodegeneration in a model of Tbk1 haploinsufficiency. We hypothesize that the consequences of Tbk1 haploinsufficiency may be highly context-dependent and require a specific synergistic stress stimulus to be uncovered.

14.
Diagnostics (Basel) ; 10(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708315

RESUMO

Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.

15.
Immunity ; 52(3): 542-556.e13, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187520

RESUMO

Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.


Assuntos
Apoptose/imunologia , Núcleo Celular/imunologia , Exossomos/imunologia , Fibrose Pulmonar/imunologia , Proteínas de Ligação a RNA/imunologia , Animais , Apoptose/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Quimiocina CXCL12/imunologia , Quimiocina CXCL12/metabolismo , Exossomos/genética , Exossomos/metabolismo , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Células NIH 3T3 , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
16.
Circulation ; 141(8): 667-677, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-31931613

RESUMO

BACKGROUND: Proinflammatory cytokines play an important role in the pathogenesis of heart failure. The mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in nonimmune cells such as cardiomyocytes remains to be elucidated. METHODS: To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Interleukin-6 signaling was inhibited by administration with its receptor antibody. Overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer. RESULTS: Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared with control littermates. Four weeks after transverse aortic constriction, the Il6 mRNA level was upregulated, but not other cytokine mRNAs, including tumor necrosis factor-α, in Regnase-1-deficient hearts. Although the Il6 mRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-interleukin-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction of Il6 mRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-interleukin-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice. CONCLUSIONS: The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.


Assuntos
Inflamação/patologia , Interleucina-6/metabolismo , Miócitos Cardíacos/metabolismo , RNA Mensageiro/metabolismo , Ribonucleases/genética , Animais , Anticorpos/imunologia , Anticorpos/uso terapêutico , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Vetores Genéticos/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/prevenção & controle , Inflamação/prevenção & controle , Interleucina-6/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-6/imunologia , Ribonucleases/deficiência , Ribonucleases/metabolismo , Regulação para Cima
17.
J Clin Invest ; 130(3): 1417-1430, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31805013

RESUMO

Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes-induced NF-κB activation and EGFRi/MEKi-mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.


Assuntos
Receptores ErbB/imunologia , Interleucina-1/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Propionibacteriaceae/imunologia , Dermatopatias Bacterianas/imunologia , Animais , Receptores ErbB/genética , Humanos , Interleucina-1/genética , Queratinócitos/imunologia , Queratinócitos/microbiologia , Queratinócitos/patologia , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/imunologia , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/imunologia , Dermatopatias Bacterianas/genética , Dermatopatias Bacterianas/patologia
18.
J Clin Exp Hematop ; 59(4): 187-195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31866620

RESUMO

The antigenic heterogeneity of the reticular framework of the white pulp and marginal zone is well documented in the human adult spleen. Immunostaining of α-smooth muscle actin characterizes the heterogeneity of the reticular framework of the white pulp and marginal zone. In the human spleen, the blood cells flow in an open circulation. T and B lymphocytes flow out from the arterial terminal, and migrate in the reticular framework. Homing of lymphocytes to lymphoid tissues is regulated by selective interactions between cell surface homing receptors and tissue vascular addressins at sites of lymphocyte recruitment from the blood. In the present study, mucosal addressin cell adhesion molecule-1 was selectively expressed on α-smooth muscle actin-positive reticular framework. The reticular framework may function in lymphocyte homing and segregation into the periarteriolar lymphoid sheath, lymph follicle and marginal zone.


Assuntos
Actinas/biossíntese , Linfócitos B/metabolismo , Moléculas de Adesão Celular/biossíntese , Regulação da Expressão Gênica , Mucoproteínas/biossíntese , Baço/metabolismo , Linfócitos T/metabolismo , Linfócitos B/ultraestrutura , Humanos , Baço/ultraestrutura , Linfócitos T/ultraestrutura
19.
J Exp Med ; 216(6): 1431-1449, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31072819

RESUMO

Regnase-1 (also known as Zc3h12a or MCPIP-1) is an endoribonuclease involved in mRNA degradation of inflammation-associated genes. Regnase-1 is inactivated in response to external stimuli through post-translational modifications including phosphorylation, yet the precise role of phosphorylation remains unknown. Here, we demonstrate that interleukin (IL)-17 induces phosphorylation of Regnase-1 in an Act1-TBK1/IKKi-dependent manner, especially in nonhematopoietic cells. Phosphorylated Regnase-1 is released from the endoplasmic reticulum (ER) into the cytosol, thereby losing its mRNA degradation function, which leads to expression of IL-17 target genes. By using CRISPR/Cas-9 technology, we generated Regnase-1 mutant mice, in which IL-17-induced Regnase-1 phosphorylation is completely blocked. Mutant mice (Regnase-1AA/AA and Regnase-1ΔCTD/ΔCTD ) were resistant to the IL-17-mediated inflammation caused by T helper 17 (Th17) cells in vivo. Thus, Regnase-1 plays a critical role in the development of IL-17-mediated inflammatory diseases via the Act1-TBK1-IKKi axis, and blockade of Regnase-1 phosphorylation sites may be promising for treatment of Th17-associated diseases.


Assuntos
Retículo Endoplasmático/metabolismo , Interleucina-17/farmacologia , Ribonucleases/metabolismo , Animais , Citosol/metabolismo , Encefalomielite Autoimune Experimental/patologia , Retículo Endoplasmático/efeitos dos fármacos , Quinase I-kappa B/metabolismo , Inflamação/patologia , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Mutação/genética , Fosforilação , Estabilidade Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleases/química , Ribonucleases/genética , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos
20.
Nat Commun ; 10(1): 1072, 2019 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-30842549

RESUMO

The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. Here, we show that Regnase-1 regulates self-renewal of HSPCs through modulating the stability of Gata2 and Tal1 mRNA. In addition, we found that dysfunction of Regnase-1 leads to the rapid onset of abnormal hematopoiesis. Thus, our data reveal that Regnase-1-mediated post-transcriptional regulation is required for HSPC maintenance and suggest that it represents a leukemia tumor suppressor.


Assuntos
Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide Aguda/genética , Processamento Pós-Transcricional do RNA/fisiologia , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo , Animais , Medula Óssea/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Autorrenovação Celular/genética , Conjuntos de Dados como Assunto , Fator de Transcrição GATA2/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HEK293 , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prognóstico , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ribonucleases/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética , Fatores de Transcrição/genética , Quimeras de Transplante
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...