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2.
Elife ; 102021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34423778

RESUMO

Macrophages undergo programmatic changes with age, leading to altered cytokine polarization and immune dysfunction, shifting these critical immune cells from protective sentinels to disease promoters. The molecular mechanisms underlying macrophage inflammaging are poorly understood. Using an unbiased RNA sequencing (RNA-seq) approach, we identified Mir146b as a microRNA whose expression progressively and unidirectionally declined with age in thioglycollate-elicited murine macrophages. Mir146b deficiency led to altered macrophage cytokine expression and reduced mitochondrial metabolic activity, two hallmarks of cellular aging. Single-cell RNA-seq identified patterns of altered inflammation and interferon gamma signaling in Mir146b-deficient macrophages. Identification of Mir146b as a potential regulator of macrophage aging provides novel insights into immune dysfunction associated with aging.

8.
Cell Rep ; 33(5): 108339, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147451

RESUMO

Here, we report our studies of immune-mediated regulation of Zika virus (ZIKV), herpes simplex virus 1 (HSV-1), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the human cornea. We find that ZIKV can be transmitted via corneal transplantation in mice. However, in human corneal explants, we report that ZIKV does not replicate efficiently and that SARS-CoV-2 does not replicate at all. Additionally, we demonstrate that type III interferon (IFN-λ) and its receptor (IFNλR1) are expressed in the corneal epithelium. Treatment of human corneal explants with IFN-λ, and treatment of mice with IFN-λ eye drops, upregulates antiviral interferon-stimulated genes. In human corneal explants, blockade of IFNλR1 enhances replication of ZIKV and HSV-1 but not SARS-CoV-2. In addition to an antiviral role for IFNλR1 in the cornea, our results suggest that the human cornea does not support SARS-CoV-2 infection despite expression of ACE2, a SARS-CoV-2 receptor, in the human corneal epithelium.


Assuntos
Betacoronavirus/fisiologia , Córnea/virologia , Infecções por Coronavirus/transmissão , Herpesvirus Humano 1/fisiologia , Interferons/imunologia , Pneumonia Viral/transmissão , Zika virus/fisiologia , Animais , Betacoronavirus/imunologia , COVID-19 , Córnea/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Herpes Simples/imunologia , Herpes Simples/transmissão , Herpes Simples/virologia , Humanos , Camundongos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , SARS-CoV-2 , Replicação Viral/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
9.
Elife ; 92020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33107823

RESUMO

Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.


Assuntos
Proteínas do Domínio Armadillo/genética , Morte Celular , Proteínas do Citoesqueleto/genética , Amaurose Congênita de Leber/patologia , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Células Fotorreceptoras de Vertebrados/patologia , Degeneração Retiniana/patologia , Animais , Proteínas do Domínio Armadillo/metabolismo , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Amaurose Congênita de Leber/genética , Masculino , Camundongos , Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo , Degeneração Retiniana/genética
10.
Transl Vis Sci Technol ; 9(10): 16, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32983624

RESUMO

Purpose: To determine whether increased growth differentiation factor 15 (GDF15) in aqueous humor (AH) is associated with worse visual field loss in patients with pseudoexfoliative glaucoma (PXG). Methods: We recruited 12 patients (6 males, 6 females) with primary open-angle glaucoma (POAG) or PXG who were scheduled to undergo glaucoma surgery. AH was obtained from the initial peripheral paracentesis for the planned glaucoma surgery, and GDF15 levels were quantified with enzyme-linked immunosorbent assay by an investigator masked to clinical information. Humphrey visual field testing was performed as a part of routine care; results were obtained by reviewing the medical record. Results: AH GDF15 was detectable in patients with POAG and PXG. Increased AH GDF15 was significantly associated with worse mean deviation in patients with POAG (r = -0.94; 95% confidence interval [CI], -0.99 to -0.33; P = 0.02) and PXG (r = -0.92; 95% CI, -0.99 to -0.41; P = 0.01). Conclusions: AH GDF15 is detectable in patients with PXG and POAG. Elevated AH GDF15 is strongly associated with worse mean deviation in both subgroups. These findings suggest that GDF15 may be a molecular marker of glaucoma severity that is generalizable to multiple types of glaucoma regardless of the underlying etiology. Translational Relevance: This study provides proof of concept that GDF15, a molecular marker of retinal ganglion stress that was initially identified in rodent models, may have clinical utility as a measure of glaucoma severity not only in POAG but also in PXG.


Assuntos
Síndrome de Exfoliação , Glaucoma , Humor Aquoso , Síndrome de Exfoliação/diagnóstico , Feminino , Fator 15 de Diferenciação de Crescimento , Humanos , Masculino , Campos Visuais
11.
Trends Mol Med ; 26(10): 892-895, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32868169

RESUMO

Optical coherence tomography angiography (OCT-A) allows noninvasive visualization of intraocular tissues with high resolution. Recently, an innovative use of this technology in studying neurodegenerative diseases has emerged with the neurosensory retina as a unique window into deeper brain tissues. Here, we discuss its role in identifying biomarkers of neurodegenerative diseases.

12.
Am J Ophthalmol ; 218: 337-341, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32387435

RESUMO

PURPOSE: To address challenges associated with identifying retinal biomarkers for Alzheimer's disease (AD) and strategies for future investigation of novel ophthalmologic biomarkers. DESIGN: Perspective. METHODS: Summarization of the current understanding of retinal changes that have been identified using advances in imaging technology, analysis of current research into how these changes reflect neurodegenerative pathology, and recommendations for further research in this area that will allow for the identification of unique biomarkers for early AD. RESULTS: Some retinal changes detectable using various imaging modalities may reflect neurodegeneration or other AD-related pathology on a cellular level. Structural changes in both the peripapillary and macular retina and changes in vascular parameters have been identified. Some imaging findings correlate with known histopathologic findings, and some are associated with cognitive decline. However, multiple challenges exist, such as identifying retinal biomarkers that are specific to biomarker-positive AD, clinical syndrome of AD, and/or pathologic AD brain, finding features that are highly sensitive and specific to AD in patients with other eye diseases, and validating potential biomarkers in population-based longitudinal cohorts. CONCLUSIONS: Further research is needed to validate retinal biomarkers for AD, with accurate classification of patients according to diagnosis and cognitive symptoms. Advances in imaging technology, big data, and machine learning, as well as carefully designed studies, will help to identify and confirm potential biomarkers and may lead to novel treatment approaches.


Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores , Doenças Retinianas/diagnóstico , Humanos , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia
14.
Cell ; 180(6): 1033, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32200797

RESUMO

VEGF-A antagonists have revolutionized wet AMD treatment. Several challenges remain including high treatment burden requiring repeated intraocular injections for persistent disease. Brolucizumab directly inhibits VEGF-A function, providing visual outcomes comparable to aflibercept (an FDA-approved VEGF-A antagonist). Anatomic retinal outcomes including retinal fluid, a marker of disease activity, favored brolucizumab. To view this Bench to Bedisde, open or download the PDF.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Degeneração Macular/imunologia , Degeneração Macular/terapia , Inibidores da Angiogênese , Humanos , Retina , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual
15.
JCI Insight ; 5(1)2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31829999

RESUMO

Effective treatments and animal models for the most prevalent neurodegenerative form of blindness in elderly people, called age-related macular degeneration (AMD), are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic pathways. Given liver X receptors (LXRs), encoded by the nuclear receptor subfamily 1 group H members 2 and 3 (NR1H3 and NR1H2), are master regulators of these pathways, herein we investigated the role of LXR in human and mouse eyes as a function of age and disease and tested the therapeutic potential of targeting LXR. We identified immunopositive LXR fragments in human extracellular early dry AMD lesions and a decrease in LXR expression within the retinal pigment epithelium (RPE) as a function of age. Aged mice lacking LXR presented with isoform-dependent ocular pathologies. Specifically, loss of the Nr1h3 isoform resulted in pathobiologies aligned with AMD, supported by compromised visual function, accumulation of native and oxidized lipids in the outer retina, and upregulation of ocular inflammatory cytokines, while absence of Nr1h2 was associated with ocular lipoidal degeneration. LXR activation not only ameliorated lipid accumulation and oxidant-induced injury in RPE cells but also decreased ocular inflammatory markers and lipid deposition in a mouse model, thereby providing translational support for pursuing LXR-active pharmaceuticals as potential therapies for dry AMD.


Assuntos
Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Degeneração Macular/genética , Degeneração Macular/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Animais , Modelos Animais de Doenças , Células Endoteliais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamação/metabolismo , Degeneração Macular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fenótipo , Retina/metabolismo , Retina/patologia , Epitélio Pigmentado da Retina , Transcriptoma , Adulto Jovem
16.
Trends Immunol ; 40(9): 825-841, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31422901

RESUMO

Macrophages are important mediators of inflammation and tissue remodeling. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in homeostasis and disease. In addition, their plasticity enables them to perform a variety of functions in response to changing tissue contexts, such as those imposed by aging. These qualities make macrophages particularly intriguing cells given their dichotomous role in protecting against, or accelerating, diseases of the cardiovascular system and the eye, two tissues that are particularly susceptible to the effects of aging. We review novel perspectives on macrophage biology, as informed by recent studies detailing the diversity of macrophage identity and function, as well as mechanisms influencing macrophage behavior that might offer opportunities for new therapeutic strategies.


Assuntos
Doenças Cardiovasculares/imunologia , Plasticidade Celular/imunologia , Oftalmopatias/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Envelhecimento/imunologia , Animais , Doenças Cardiovasculares/patologia , Oftalmopatias/patologia , Homeostase/imunologia , Humanos
17.
Exp Eye Res ; 187: 107775, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449793

RESUMO

Cell-autonomous endothelial cell (EC) fibroblast growth factor receptor (FGFR) signaling through FGFR1/2 is essential for injury-induced wound vascularization and pathologic neovascularization as in blinding eye diseases such as age-related macular degeneration. Which FGF ligand(s) is critical in regulating angiogenesis is unknown. Utilizing ex vivo models of choroidal endothelial sprouting and in vivo models of choroidal neovascularization (CNV), we demonstrate here that only FGF2 is the essential ligand. Though FGF-FGFR signaling can activate multiple intracellular signaling pathways, we show that FGF2 regulates pathogenic angiogenesis via STAT3 activation. The identification of FGF2 as a critical mediator in aberrant neovascularization provides a new opportunity for developing multi-target therapies in blinding eye diseases especially given the limitations of anti-VEGF monotherapy.


Assuntos
Corioide/irrigação sanguínea , Neovascularização de Coroide/etiologia , Células Endoteliais/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Western Blotting , Proliferação de Células , Células Cultivadas , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Injeções Intravítreas , Camundongos , Camundongos Endogâmicos C57BL
18.
Cell Metab ; 30(2): 329-342.e5, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31204283

RESUMO

Aging is a significant risk factor for impaired tissue functions and chronic diseases. Age-associated decline in systemic NAD+ availability plays a critical role in regulating the aging process across many species. Here, we show that the circulating levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) significantly decline with age in mice and humans. Increasing circulating eNAMPT levels in aged mice by adipose-tissue-specific overexpression of NAMPT increases NAD+ levels in multiple tissues, thereby enhancing their functions and extending healthspan in female mice. Interestingly, eNAMPT is carried in extracellular vesicles (EVs) through systemic circulation in mice and humans. EV-contained eNAMPT is internalized into cells and enhances NAD+ biosynthesis. Supplementing eNAMPT-containing EVs isolated from young mice significantly improves wheel-running activity and extends lifespan in aged mice. Our findings have revealed a novel EV-mediated delivery mechanism for eNAMPT, which promotes systemic NAD+ biosynthesis and counteracts aging, suggesting a potential avenue for anti-aging intervention in humans.


Assuntos
Envelhecimento , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Longevidade , Nicotinamida Fosforribosiltransferase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade
19.
Ophthalmol Retina ; 3(6): 510-515, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31174673

RESUMO

PURPOSE: To determine the presence and to characterize location of retinal vascular lesions in patients with hereditary hemorrhagic telangiectasia (HHT). DESIGN: Prospective cross-sectional pilot descriptive study. PARTICIPANTS: Eighteen patients (age range, 22-65 years) with a clinical diagnosis of HHT. METHODS: Patients completed the 25-item National Eye Institute Visual Function Questionnaire and underwent a single study visit with dilated ophthalmic examination, OCT angiography (OCTA), and fluorescein angiography (FA) with widefield imaging. MAIN OUTCOME MEASURES: Presence of retinal vascular abnormalities in 1 or more quadrants identified on widefield FA, Visual Function Questionnaire scores, retinal vessel architecture on FA and OCTA, and dilated ophthalmic examination findings. RESULTS: Of the 18 patients recruited, fine telangiectatic vessels with capillary dilation and tortuosity were identified in 78% by FA imaging. CONCLUSIONS: In the first FA and OCTA analysis of the retina of unrelated HHT patients, we found a high rate of temporal and nasal telangiectasias. These telangiectasias were more apparent in older patients, suggesting that they may appear in later stages of HHT development. No abnormalities of the macular vasculature and architecture were identified, explaining the generally well-preserved visual acuity. Temporal and nasal telangiectasias may have clinical significance in a patient's risk for retinal hemorrhage and likely warrant periodic surveillance by annual FA imaging.


Assuntos
Angiofluoresceinografia/métodos , Doenças Retinianas/diagnóstico , Vasos Retinianos/patologia , Telangiectasia Hemorrágica Hereditária/complicações , Tomografia de Coerência Óptica/métodos , Acuidade Visual , Adolescente , Adulto , Idoso , Capilares/patologia , Estudos Transversais , Feminino , Seguimentos , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Doenças Retinianas/etiologia , Telangiectasia Hemorrágica Hereditária/diagnóstico , Adulto Jovem
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