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1.
J Clin Invest ; 133(4)2023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36787231

RESUMEN

Pathological neovascularization in age-related macular degeneration (nvAMD) drives the principal cause of blindness in the elderly. While there is a robust genetic association between genes of innate immunity and AMD, genome-to-phenome relationships are low, suggesting a critical contribution of environmental triggers of disease. Possible insight comes from the observation that a past history of infection with pathogens such as Chlamydia pneumoniae, or other systemic inflammation, can predispose to nvAMD in later life. Using a mouse model of nvAMD with prior C. pneumoniae infection, endotoxin exposure, and genetic ablation of distinct immune cell populations, we demonstrated that peripheral infections elicited epigenetic reprogramming that led to a persistent memory state in retinal CX3CR1+ mononuclear phagocytes (MNPs). The immune imprinting persisted long after the initial inflammation had subsided and ultimately exacerbated choroidal neovascularization in a model of nvAMD. Single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) identified activating transcription factor 3 (ATF3) as a central mediator of retina-resident MNP reprogramming following peripheral inflammation. ATF3 polarized MNPs toward a reparative phenotype biased toward production of proangiogenic factors in response to subsequent injury. Therefore, a past history of bacterial endotoxin-induced inflammation can lead to immunological reprograming within CNS-resident MNPs and aggravate pathological angiogenesis in the aging retina.


Asunto(s)
Neovascularización Coroidal , Degeneración Macular , Humanos , Microglía/patología , Retina/patología , Neovascularización Coroidal/genética , Degeneración Macular/genética , Degeneración Macular/patología , Inflamación/patología
2.
Science ; 379(6627): 45-62, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36603072

RESUMEN

Age-related macular degeneration is a prevalent neuroinflammatory condition and a major cause of blindness driven by genetic and environmental factors such as obesity. In diseases of aging, modifiable factors can be compounded over the life span. We report that diet-induced obesity earlier in life triggers persistent reprogramming of the innate immune system, lasting long after normalization of metabolic abnormalities. Stearic acid, acting through Toll-like receptor 4 (TLR4), is sufficient to remodel chromatin landscapes and selectively enhance accessibility at binding sites for activator protein-1 (AP-1). Myeloid cells show less oxidative phosphorylation and shift to glycolysis, ultimately leading to proinflammatory cytokine transcription, aggravation of pathological retinal angiogenesis, and neuronal degeneration associated with loss of visual function. Thus, a past history of obesity reprograms mononuclear phagocytes and predisposes to neuroinflammation.


Asunto(s)
Memoria Epigenética , Inmunidad Innata , Degeneración Macular , Enfermedades Neuroinflamatorias , Obesidad , Animales , Ratones , Citocinas/genética , Inmunidad Innata/genética , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/inmunología , Obesidad/genética , Fagocitos/inmunología , Transcripción Genética , Degeneración Macular/genética , Degeneración Macular/inmunología , Reprogramación Celular/genética , Receptor Toll-Like 4/genética
3.
Cell Metab ; 33(4): 818-832.e7, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33548171

RESUMEN

Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.


Asunto(s)
Senescencia Celular , Enfermedades de la Retina/patología , Proteína bcl-X/metabolismo , Animales , Apoptosis/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/deficiencia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Flavonoles/química , Flavonoles/farmacología , Flavonoles/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Patológica , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/metabolismo , Tacrolimus/análogos & derivados , Tacrolimus/farmacología , Proteína bcl-X/antagonistas & inhibidores
4.
Science ; 369(6506)2020 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-32820093

RESUMEN

In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.


Asunto(s)
Envejecimiento/patología , Retinopatía Diabética/patología , Trampas Extracelulares/inmunología , Vasos Retinianos/patología , Animales , Senescencia Celular , Retinopatía Diabética/inmunología , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Vasos Retinianos/inmunología
5.
Proc Natl Acad Sci U S A ; 116(10): 4538-4547, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30787185

RESUMEN

Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from ß-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.


Asunto(s)
Permeabilidad Capilar , Retinopatía Diabética/patología , Receptor Notch1/metabolismo , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Animales , Antígenos CD/metabolismo , Cadherinas/metabolismo , Proteínas de Unión al Calcio/biosíntesis , Activación Enzimática , Hiperglucemia/metabolismo , Proteína Jagged-1/biosíntesis , Ratones , Óxido Nítrico/biosíntesis , Vasos Retinianos/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Familia-src Quinasas/metabolismo
6.
Sci Transl Med ; 8(362): 362ra144, 2016 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-27797960

RESUMEN

Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.


Asunto(s)
Senescencia Celular , Retinopatía Diabética/sangre , Neovascularización Patológica , Vasos Retinianos/patología , Animales , Línea Celular Tumoral , Proliferación Celular , Citocinas/metabolismo , Retinopatía Diabética/fisiopatología , Estrés del Retículo Endoplásmico , Endorribonucleasas/metabolismo , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Oxígeno/química , Fenotipo , Proteínas Serina-Treonina Quinasas/metabolismo , Retina/patología , Neovascularización Retiniana , Factor A de Crecimiento Endotelial Vascular/metabolismo , Vitrectomía
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