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1.
EMBO J ; 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39349844

RESUMO

Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.

2.
Nature ; 592(7852): 138-143, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33731925

RESUMO

A variety of species of bacteria are known to colonize human tumours1-11, proliferate within them and modulate immune function, which ultimately affects the survival of patients with cancer and their responses to treatment12-14. However, it is not known whether antigens derived from intracellular bacteria are presented by the human leukocyte antigen class I and II (HLA-I and HLA-II, respectively) molecules of tumour cells, or whether such antigens elicit a tumour-infiltrating T cell immune response. Here we used 16S rRNA gene sequencing and HLA peptidomics to identify a peptide repertoire derived from intracellular bacteria that was presented on HLA-I and HLA-II molecules in melanoma tumours. Our analysis of 17 melanoma metastases (derived from 9 patients) revealed 248 and 35 unique HLA-I and HLA-II peptides, respectively, that were derived from 41 species of bacteria. We identified recurrent bacterial peptides in tumours from different patients, as well as in different tumours from the same patient. Our study reveals that peptides derived from intracellular bacteria can be presented by tumour cells and elicit immune reactivity, and thus provides insight into a mechanism by which bacteria influence activation of the immune system and responses to therapy.


Assuntos
Antígenos de Bactérias/análise , Antígenos de Bactérias/imunologia , Bactérias/imunologia , Antígenos HLA/imunologia , Melanoma/imunologia , Melanoma/microbiologia , Peptídeos/análise , Peptídeos/imunologia , Apresentação de Antígeno , Bactérias/classificação , Bactérias/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Antígenos HLA/análise , Humanos , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Melanoma/patologia , Metástase Neoplásica/imunologia , Filogenia , RNA Ribossômico 16S/genética
3.
Gut ; 71(2): 345-355, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33649045

RESUMO

OBJECTIVE: Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development. DESIGN: To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment. RESULTS: We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma. CONCLUSIONS: These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.


Assuntos
Adenocarcinoma/patologia , Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Senoterapia/uso terapêutico , Adenocarcinoma/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Neoplasias Pancreáticas/metabolismo , Lesões Pré-Cancerosas/metabolismo
4.
Immunol Cell Biol ; 96(3): 284-297, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29356071

RESUMO

Inflammation plays pivotal roles in different stages of tumor development. Screening for predisposing genetic abnormalities and understanding the roles these genes play in the crosstalk between immune and cancer cells will provide new targets for cancer therapy and prevention. The interferon inducible transmembrane (IFITM) genes are involved in pathogenesis of the gastro-intestinal tract. We aimed at delineating the role of IFITM3 in colonic epithelial homeostasis, inflammation and colitis-associated tumorigenesis using IFITM3-deficient mice. Chemical induction of colitis in IFITM3-deficient mice results in significantly increased clinical signs of inflammation and induction of invasive tumorigenesis. Bone marrow transplantation showed that cells of the hematopoietic system are responsible for colitis deterioration. In these mice, impaired cytokine expression skewed inflammatory response toward pathogenic Th17 with reduced expression of the anti-inflammatory cytokine IL10 during the recovery phase. Intriguingly, mice lacking the entire IFITM locus developed spontaneous chronic colitis from the age of 14 weeks. Sequencing the 16S rRNA of naïve mice lacking IFITM3 gene, or the entire locus containing five IFITM genes, revealed these mice had significant bacterial differences from their wild-type littermates. Our novel results provide strong evidence for the essential role of IFITM genes in ameliorating colitis and colitis-associated tumorigenesis.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Colite/imunologia , Colite/microbiologia , Imunidade , Inflamação/genética , Proteínas de Membrana/genética , Microbiota , Animais , Colite/genética , Colite/patologia , Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Hematopoese , Imunidade/genética , Proteínas de Membrana/deficiência , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/genética , Células Mieloides/patologia
5.
Nat Cell Biol ; 26(8): 1336-1345, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39103548

RESUMO

The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.


Assuntos
Antígeno B7-H1 , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina , Estabilidade Proteica , Senescência Celular/imunologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Animais , Humanos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Vigilância Imunológica , Camundongos Endogâmicos C57BL , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/genética , Camundongos , Proteólise , Receptores de IgG/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/genética
6.
Aging (Albany NY) ; 15(7): 2395-2417, 2023 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-36996500

RESUMO

Cellular senescence is a stable state of cell cycle arrest that regulates tissue integrity and protects the organism from tumorigenesis. However, the accumulation of senescent cells during aging contributes to age-related pathologies. One such pathology is chronic lung inflammation. p21 (CDKN1A) regulates cellular senescence via inhibition of cyclin-dependent kinases (CDKs). However, its role in chronic lung inflammation and functional impact on chronic lung disease, where senescent cells accumulate, is less understood. To elucidate the role of p21 in chronic lung inflammation, we subjected p21 knockout (p21-/-) mice to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to chronic bronchitis and accumulation of senescent cells. p21 knockout led to a reduced presence of senescent cells, alleviated the pathological manifestations of chronic lung inflammation, and improved the fitness of the mice. The expression profiling of the lung cells revealed that resident epithelial and endothelial cells, but not immune cells, play a significant role in mediating the p21-dependent inflammatory response following chronic LPS exposure. Our results implicate p21 as a critical regulator of chronic bronchitis and a driver of chronic airway inflammation and lung destruction.


Assuntos
Bronquite Crônica , Pneumonia , Camundongos , Animais , Células Endoteliais/metabolismo , Bronquite Crônica/genética , Lipopolissacarídeos/toxicidade , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pneumonia/metabolismo , Ciclo Celular , Senescência Celular/fisiologia , Inflamação
7.
Dev Cell ; 48(1): 115-125.e4, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30503750

RESUMO

Pancreatic beta cells have been shown to be heterogeneous at multiple levels. However, spatially interrogating transcriptional heterogeneity in the intact tissue has been challenging. Here, we developed an optimized protocol for single-molecule transcript imaging in the intact pancreas and used it to identify a sub-population of "extreme" beta cells with elevated mRNA levels of insulin and other secretory genes. Extreme beta cells contain higher ribosomal and proinsulin content but lower levels of insulin protein in fasted states, suggesting they may be tuned for basal insulin secretion. They exhibit a distinctive intra-cellular polarization pattern, with elevated mRNA concentrations in an apical ER-enriched compartment, distinct from the localization of nascent and mature proteins. The proportion of extreme cells increases in db/db diabetic mice, potentially facilitating the required increase in basal insulin. Our results thus highlight a sub-population of beta cells that may carry distinct functional roles along physiological and pathological timescales.


Assuntos
Heterogeneidade Genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Pâncreas/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Secreção de Insulina/fisiologia , Camundongos Transgênicos , Proinsulina/metabolismo
8.
Cell Rep ; 22(13): 3468-3479, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29590616

RESUMO

The tumor suppressor p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest, and senescence. Although p53 is known to limit inflammation during tumor development, its role in regulating chronic lung inflammation is less well understood. To elucidate the function of airway epithelial p53 in such inflammation, we subjected genetically modified mice, whose bronchial epithelial club cells lack p53, to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to severe chronic bronchitis and airway senescence in wild-type mice. Surprisingly, the club cell p53 knockout mice exhibited reduced airway senescence and bronchitis in response to chronic LPS exposure and were significantly protected from global lung destruction. Furthermore, pharmacological elimination of senescent cells also protected wild-type mice from chronic LPS-induced bronchitis. Our results implicate p53 in induction of club-cell senescence and correlate epithelial cell senescence of chronic airway inflammation and lung destruction.


Assuntos
Brônquios/metabolismo , Pneumonia/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Brônquios/patologia , Senescência Celular/fisiologia , Doença Crônica , Progressão da Doença , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/patologia
9.
Aging Cell ; 16(4): 661-671, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28455874

RESUMO

Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo.


Assuntos
Envelhecimento/genética , Senescência Celular/genética , Neoplasias/genética , Análise de Célula Única/métodos , Coloração e Rotulagem/métodos , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Biomarcadores/análise , Senescência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Etoposídeo/farmacologia , Fibrose , Citometria de Fluxo , Expressão Gênica , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Linfócitos/metabolismo , Linfócitos/patologia , Camundongos , Imagem Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Cultura Primária de Células , Células Estromais/metabolismo , Células Estromais/patologia , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
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