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1.
J Exp Med ; 217(7)2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32311008

RESUMO

Antiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 mo and is largely composed of clones of infected CD4+ T cells. The long half-life appears to result in part from expansion and contraction of infected CD4+ T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen-responsive CD4+ T cells containing defective or intact latent proviruses were found in seven of eight individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4+ T cells.


Assuntos
Antígenos Virais/imunologia , Linfócitos T CD4-Positivos/imunologia , Reservatórios de Doenças/virologia , HIV-1/fisiologia , Proliferação de Células , Células Clonais , Humanos , Filogenia , Provírus
2.
Cell Stem Cell ; 26(3): 346-358.e4, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-31978363

RESUMO

Lung injury activates specialized adult epithelial progenitors to regenerate the epithelium. Depending on the extent of injury, both remaining alveolar type II cells (AEC2s) and distal airway stem/progenitors mobilize to cover denuded alveoli and restore normal barriers. The major source of airway stem/progenitors other than basal-like cells remains uncertain. Here, we define a distinct subpopulation (∼5%) of club-like lineage-negative epithelial progenitors (LNEPs) marked by high H2-K1 expression critical for alveolar repair. Quiescent H2-K1high cells account for virtually all in vitro regenerative activity of airway lineages. After bleomycin injury, H2-K1 cells expand and differentiate in vivo to alveolar lineages. However, injured H2-K1 cells eventually develop impaired self-renewal with features of senescence, limiting complete repair. Normal H2-K1high cells transplanted into injured lungs differentiate into alveolar cells and rescue lung function. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and are a potential therapeutic adjunct after major lung injury.


Assuntos
Células Epiteliais , Lesão Pulmonar , Células Epiteliais Alveolares , Diferenciação Celular , Humanos , Pulmão , Células-Tronco
3.
JCI Insight ; 4(24)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31687975

RESUMO

Accumulation of senescent cells is associated with the progression of pulmonary fibrosis, but mechanisms accounting for this linkage are not well understood. To explore this issue, we investigated whether a class of biologically active profibrotic lipids, the leukotrienes (LT), is part of the senescence-associated secretory phenotype. The analysis of conditioned medium (CM), lipid extracts, and gene expression of LT biosynthesis enzymes revealed that senescent cells secreted LT, regardless of the origin of the cells or the modality of senescence induction. The synthesis of LT was biphasic and followed by antifibrotic prostaglandin (PG) secretion. The LT-rich CM of senescent lung fibroblasts (IMR-90) induced profibrotic signaling in naive fibroblasts, which were abrogated by inhibitors of ALOX5, the principal enzyme in LT biosynthesis. The bleomycin-induced expression of genes encoding LT and PG synthases, level of cysteinyl LT in the bronchoalveolar lavage, and overall fibrosis were reduced upon senescent cell removal either in a genetic mouse model or after senolytic treatment. Quantification of ALOX5+ cells in lung explants obtained from idiopathic pulmonary fibrosis (IPF) patients indicated that half of these cells were also senescent (p16Ink4a+). Unlike human fibroblasts from unused donor lungs made senescent by irradiation, senescent IPF fibroblasts secreted LTs but failed to synthesize PGs. This study demonstrates for the first time to our knowledge that senescent cells secrete functional LTs, significantly contributing to the LT pool known to cause or exacerbate IPF.


Assuntos
Senescência Celular , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/patologia , Leucotrienos/metabolismo , Pulmão/patologia , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular , Meios de Cultivo Condicionados/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibroblastos/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Leucotrienos/análise , Inibidores de Lipoxigenase/farmacologia , Pulmão/citologia , Masculino , Camundongos , Cultura Primária de Células , Prostaglandinas/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
J Clin Invest ; 127(10): 3675-3688, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28872461

RESUMO

TGF-ß1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-ß1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-ß1-induced epithelial-mesenchymal transition without immediate TGF-ß1 receptor (TßR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-ß1 responses (IC50 ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TßRI kinase. Combined inhibition of LOXL2 and TßRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TßRI kinase in LOXL2-expressing cells.


Assuntos
Inibidores Enzimáticos , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Neoplasias Pulmonares , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fibrose Pulmonar , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Metástase Neoplásica , Proteínas de Neoplasias/genética , Fenóis/química , Fenóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/genética
5.
Nat Cell Biol ; 19(8): 904-914, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28737769

RESUMO

After influenza infection, lineage-negative epithelial progenitors (LNEPs) exhibit a binary response to reconstitute epithelial barriers: activating a Notch-dependent ΔNp63/cytokeratin 5 (Krt5) remodelling program or differentiating into alveolar type II cells (AEC2s). Here we show that local lung hypoxia, through hypoxia-inducible factor (HIF1α), drives Notch signalling and Krt5pos basal-like cell expansion. Single-cell transcriptional profiling of human AEC2s from fibrotic lungs revealed a hypoxic subpopulation with activated Notch, suppressed surfactant protein C (SPC), and transdifferentiation toward a Krt5pos basal-like state. Activated murine Krt5pos LNEPs and diseased human AEC2s upregulate strikingly similar core pathways underlying migration and squamous metaplasia. While robust, HIF1α-driven metaplasia is ultimately inferior to AEC2 reconstitution in restoring normal lung function. HIF1α deletion or enhanced Wnt/ß-catenin activity in Sox2pos LNEPs blocks Notch and Krt5 activation, instead promoting rapid AEC2 differentiation and migration and improving the quality of alveolar repair.


Assuntos
Linhagem da Célula , Proliferação de Células , Transdiferenciação Celular , Células Epiteliais/metabolismo , Hipóxia/metabolismo , Influenza Humana/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Oxigênio/metabolismo , Alvéolos Pulmonares/metabolismo , Regeneração , Animais , Movimento Celular , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Hipóxia/genética , Hipóxia/patologia , Hipóxia/virologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/genética , Influenza Humana/patologia , Influenza Humana/virologia , Queratina-5/genética , Queratina-5/metabolismo , Masculino , Camundongos Transgênicos , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Fenótipo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Receptores Notch/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Análise de Célula Única , Fatores de Tempo , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Via de Sinalização Wnt
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