RESUMO
MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. We recently demonstrated that levels of miR-106b were significantly decreased in the vitreous and plasma of patients with neovascular age-related macular degeneration (AMD). Here we show that expression of the miR-106b-25 cluster is negatively regulated by the unfolded protein response pathway of protein kinase RNA-like ER kinase (PERK) in a mouse model of neovascular AMD. A reduction in levels of miR-106b triggers vascular growth both in vivo and in vitro by inducing production of pro-angiogenic factors. We demonstrate that therapeutic delivery of miR-106b to the retina with lentiviral vectors protects against aberrant retinal angiogenesis in two distinct mouse models of pathological retinal neovascularization. Results from this study suggest that miRNAs such as miR-106b have the potential to be used as multitarget therapeutics for conditions characterized by pathological retinal angiogenesis.
Assuntos
Neovascularização de Coroide/genética , Degeneração Macular/genética , MicroRNAs/genética , Neovascularização Retiniana/genética , Animais , Linhagem Celular , Movimento Celular/genética , Neovascularização de Coroide/patologia , Retinopatia Diabética , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Células Endoteliais , Queimaduras Oculares , Humanos , Terapia a Laser , Degeneração Macular/patologia , Camundongos , Oxigênio/toxicidade , Neovascularização Retiniana/patologia , Retinopatia da Prematuridade , Resposta a Proteínas não Dobradas/genética , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismoRESUMO
Obesity gives rise to metabolic complications by mechanisms that are poorly understood. Although chronic inflammatory signaling in adipose tissue is typically associated with metabolic deficiencies linked to excessive weight gain, we identified a subset of neuropilin-1 (NRP1)-expressing myeloid cells that accumulate in adipose tissue and protect against obesity and metabolic syndrome. Ablation of NRP1 in macrophages compromised lipid uptake in these cells, which reduced substrates for fatty acid ß-oxidation and shifted energy metabolism of these macrophages toward a more inflammatory glycolytic metabolism. Conditional deletion of NRP1 in LysM Cre-expressing cells leads to inadequate adipose vascularization, accelerated weight gain, and reduced insulin sensitivity even independent of weight gain. Transfer of NRP1+ hematopoietic cells improved glucose homeostasis, resulting in the reversal of a prediabetic phenotype. Our findings suggest a pivotal role for adipose tissue-resident NRP1+-expressing macrophages in driving healthy weight gain and maintaining glucose tolerance.
Assuntos
Tecido Adiposo/metabolismo , Macrófagos/metabolismo , Neuropilina-1/metabolismo , Animais , Síndrome Metabólica/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/metabolismoRESUMO
Phagocytosis and elimination of shed aged photoreceptor outer segments (POS) by retinal pigment epithelial cells is crucial for photoreceptor function and survival. Genetic studies on a natural animal model of recessive retinal degeneration allowed the identification of MerTK, the gene encoding the surface receptor required for POS internalization. Following this discovery, screenings of DNA samples from patients have revealed that MERTK mutations cause retinal degenerations in humans. MERTK patients present some of the classical symptoms of retinitis pigmentosa, but it is atypical in that the disease develops very early during childhood and the macula is also involved early on. Therefore, the phenotype ought to be qualified as a rod-cone dystrophy. Recently, MERTK has been implicated in various types of cancers and sclerosis. This review identifies the different MERTK mutations known so far and describes associated pathologies.
Assuntos
Predisposição Genética para Doença/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Degeneração Retiniana/genética , Animais , Modelos Animais de Doenças , Humanos , Fagocitose/genética , Proto-Oncogene Mas , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , c-Mer Tirosina QuinaseRESUMO
Phagocytosis of apoptotic cells by macrophages and spent photoreceptor outer segments (POS) by retinal pigment epithelial (RPE) cells requires several proteins, including MerTK receptors and associated Gas6 and protein S ligands. In the retina, POS phagocytosis is rhythmic, and MerTK is activated promptly after light onset via the αvß5 integrin receptor and its ligand MFG-E8, thus generating a phagocytic peak. The phagocytic burst is limited in time, suggesting a down-regulation mechanism that limits its duration. Our previous data showed that MerTK helps control POS binding of integrin receptors at the RPE cell surface as a negative feedback loop. Our present results show that a soluble form of MerTK (sMerTK) is released in the conditioned media of RPE-J cells during phagocytosis and in the interphotoreceptor matrix of the mouse retina during the morning phagocytic peak. In contrast to macrophages, the two cognate MerTK ligands have an opposite effect on phagocytosis and sMerTK release, whereas the integrin ligand MFG-E8 markedly increases both phagocytosis and sMerTK levels. sMerTK acts as a decoy receptor blocking the effect of both MerTK ligands. Interestingly, stimulation of sMerTK release decreases POS binding. Conversely, blocking MerTK cleavage increased mostly POS binding by RPE cells. Therefore, our data suggest that MerTK cleavage contributes to the acute regulation of RPE phagocytosis by limiting POS binding to the cell surface.