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1.
Elife ; 82019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31414985

RESUMO

Whether complement dysregulation directly contributes to the pathogenesis of peripheral nervous system diseases, including sensory neuropathies, is unclear. We addressed this important question in a mouse model of ocular HSV-1 infection, where sensory nerve damage is a common clinical problem. Through genetic and pharmacologic targeting, we uncovered a central role for C3 in sensory nerve damage at the morphological and functional levels. Interestingly, CD4 T cells were central in facilitating this complement-mediated damage. This same C3/CD4 T cell axis triggered corneal sensory nerve damage in a mouse model of ocular graft-versus-host disease (GVHD). However, this was not the case in a T-dependent allergic eye disease (AED) model, suggesting that this inflammatory neuroimmune pathology is specific to certain disease etiologies. Collectively, these findings uncover a central role for complement in CD4 T cell-dependent corneal nerve damage in multiple disease settings and indicate the possibility for complement-targeted therapeutics to mitigate sensory neuropathies.

2.
Proc Natl Acad Sci U S A ; 116(26): 13087-13096, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189593

RESUMO

Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor's ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

3.
Immunity ; 50(3): 723-737.e7, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30850344

RESUMO

Microglia from different nervous system regions are molecularly and anatomically distinct, but whether they also have different functions is unknown. We combined lineage tracing, single-cell transcriptomics, and electrophysiology of the mouse retina and showed that adult retinal microglia shared a common developmental lineage and were long-lived but resided in two distinct niches. Microglia in these niches differed in their interleukin-34 dependency and functional contribution to visual-information processing. During certain retinal-degeneration models, microglia from both pools relocated to the subretinal space, an inducible disease-associated niche that was poorly accessible to monocyte-derived cells. This microglial transition involved transcriptional reprogramming of microglia, characterized by reduced expression of homeostatic checkpoint genes and upregulation of injury-responsive genes. This transition was associated with protection of the retinal pigmented epithelium from damage caused by disease. Together, our data demonstrate that microglial function varies by retinal niche, thereby shedding light on the significance of microglia heterogeneity.


Assuntos
Homeostase/fisiologia , Microglia/patologia , Degeneração Retiniana/patologia , Animais , Modelos Animais de Doenças , Epitélio Anterior/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Retina/patologia , Regulação para Cima/fisiologia
4.
Methods Mol Biol ; 1834: 153-164, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30324443

RESUMO

With the new understanding that adult microglia in mice have embryonic origins and are maintained in situ throughout life, it has become pertinent to now understand how these unique cells differ from monocyte-derived macrophages. The latter are recruited into the neural retina (and elsewhere in CNS) in certain diseased states, such as in various forms of retinal degeneration. However, phenotypic markers expressed by microglia and monocyte-derived macrophages largely overlap, thereby making it technically challenging to distinguish the two cell types in disease. To address this problem in mice, we have established an in vivo fate mapping system that enables distinguishing these two cell types in retinal disease models. Our approach leverages the seminal work that originally developed Cx3cr1-CreER mice and is based on commercially available mouse strains. Here, we detail our protocol and how to apply this fate mapping method paired with flow cytometry (or immunohistochemistry) to faithfully distinguish and examine microglia vs. monocyte-derived macrophages in a mutually exclusive manner. This approach will henceforth empower new efforts to identify functional specializations of these two populations in the pathobiology of retinal degenerative diseases and possibly other conditions of the retina where monocyte recruitment is observed, such as in glaucoma, diabetic retinopathy, ischemia reperfusion, retinal detachment, and so on.


Assuntos
Macrófagos/metabolismo , Microglia/metabolismo , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo , Animais , Biomarcadores , Sobrevivência Celular , Modelos Animais de Doenças , Citometria de Fluxo , Expressão Gênica , Genes Reporter , Leucócitos/imunologia , Leucócitos/metabolismo , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Microglia/imunologia , Microscopia Confocal , Doenças Retinianas/patologia
5.
Prog Retin Eye Res ; 70: 85-98, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30552975

RESUMO

In the eye immune defenses must take place in a plethora of differing microenvironments ranging from the corneal and conjunctival epithelia facing the external environment to the pigmented connective tissue of the uveal tract containing smooth muscle, blood vessels and peripheral nerves to the innermost and highly protected neural retina. The extravascular environment of the neural retina, like the brain parenchyma, is stringently controlled to maintain conditions required for neural transmission. The unique physiological nature of the neural retina can be attributed to the blood retinal barriers (BRB) of the retinal vasculature and the retinal pigment epithelium, which both tightly regulate the transport of small molecules and restrict passage of cells and macromolecules from the circulation into the retina in a similar fashion to the blood brain barrier (BBB). The extracellular environment of the neural retina differs markedly from that of the highly vascular, loose connective tissue of the choroid, which lies outside the BRB. The choroid hosts a variety of immune cell types, including macrophages, dendritic cells (DCs) and mast cells. This is in marked contrast to the neural parenchyma of the retina, which is populated almost solely by microglia. This review will describe the current understanding of the distribution, phenotype and physiological role of ocular immune cells behind or inside the blood-retinal barriers and those in closely juxtaposed tissues outside the barrier. The nature and function of these immune cells can profoundly influence retinal homeostasis and lead to disordered immune function that can lead to vision loss.

6.
Mucosal Immunol ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279513

RESUMO

Severe, chronic eye allergy is an understudied, vision-threatening condition. Treatments remain limited. We used a mouse model of severe allergic eye disease (AED) to determine whether topical application of the pro-resolution mediator Resolvin D1 (RvD1) terminates the response. AED was induced by injection of ovalbumin (OVA) followed by topical challenge of OVA daily. RvD1 was applied topically prior to OVA. Clinical symptoms were scored. Eye washes were assayed for MUC5AC. After 7 days, eyes were removed and the number of goblet cells, T helper cell responses and presence of immune cells in draining lymph nodes and conjunctiva determined. Topical RvD1 treatment significantly reduced symptoms of AED. RvD1 did not alter the systemic type 2 immune response in the lymph nodes. AED increased the total amount of goblet cell mucin secretion, but not the number of goblet cells. RvD1 prevented this increase, but did not alter goblet cell number. Absolute numbers of CD4 + T cells, total CD11b + myeloid cells, eosinophils, neutrophils, and monocytes, but not macrophages increased in AED versus RvD1-treated mice. We conclude that topical application of RvD1 reduced the ocular allergic response by local actions in conjunctival immune response and a decrease in goblet cell mucin secretion.

7.
JCI Insight ; 3(19)2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30282825

RESUMO

Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HCT). The tyrosine kinase SYK contributes to both acute and chronic GVHD development, making it an attractive target for GVHD prevention. Entospletinib (ENTO) is a second-generation highly selective SYK inhibitor with a high safety profile. Potential utility of ENTO as GVHD prophylaxis in patients was examined using a preclinical mouse model of eye and skin GVHD and ENTO-compounded chow. We found that early SYK inhibition improved blood immune cell reconstitution in GVHD mice and prolonged survival, with 60% of mice surviving to day +120 compared with 10% of mice treated with placebo. Compared with mice receiving placebo, mice receiving ENTO had dramatic improvements in clinical eye scores, alopecia scores, and skin scores. Infiltrating SYK+ cells expressing B220 or F4/80, resembling SYK+ cells found in lichenoid skin lesions of chronic GVHD patients, were abundant in the skin of placebo mice but were rare in ENTO-treated mice. Thus, ENTO given early after HCT safely prevented GVHD.

8.
Sci Transl Med ; 10(451)2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30045980

RESUMO

Meibomian glands (MGs) are sebaceous glands of the eyelid margin that secrete lipids needed to avert tear evaporation and to help maintain ocular surface homeostasis. Obstruction of MGs or other forms of MG dysfunction can promote chronic diseases of the ocular surface. Although chronic eyelid inflammation, such as allergic eye disease, is an associated risk factor for obstructive MG dysfunction, it is not clear whether inflammatory processes contribute to the pathophysiology of MG obstruction. We show that polymorphonuclear neutrophils (PMNs) promoted MG obstruction in a chronic inflammatory model of allergic eye disease in mice. Analysis of leukocytes in tears of patients with MG dysfunction showed an increase in PMN numbers compared to healthy subjects. Moreover, PMN numbers in tears positively correlated with clinical severity of MG dysfunction. Our findings point to a role for PMNs in the pathogenesis and progression of MG dysfunction.

9.
Methods Mol Biol ; 1799: 49-57, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29956143

RESUMO

Ocular IgE-associated allergy ranges from mild disease (seasonal and perennial allergic conjunctivitis) to more chronic/severe and vision-threatening forms (atopic and vernal keratoconjunctivitis). Whereas mild forms of disease have been studied extensively, less is known about the more chronic forms. Our lab has helped to address this knowledge gap by developing and characterizing an allergen-induced, chronic/severe, IgE-associated model of ocular allergy referred to as the severe allergic eye disease (AED) model. It is distinct from previously described models that mimic the more mild forms, referred to in the literature as the allergic conjunctivitis (AC) model. The purpose of this method article is to detail the protocol to induce and characterize the AED model and directly compare these mice to the mild AC model. Troubleshooting and implications are also discussed.

10.
Cell Immunol ; 330: 79-85, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29703455

RESUMO

The number of neurons dedicated to vision itself is thought to be greater than the sum of the four other senses combined. Yet, little attention has been payed to the retina as compared to elsewhere in the central nervous system with respect to microglia, the macrophages of the neural parenchyma. Indeed, major advancements in the understanding of microglial ontogeny and maintenance in brain and spinal cord are now widely appreciated, whereas less notice has been given to the neural retina in this regard. The current Review covers topical concepts on adult microglia and perivascular macrophage ontogenies in the steady state retina, as well as parallels made with these macrophages in other areas of the central nervous system. The subject of recruited monocytes and their descendant monocyte-derived macrophages in degenerative diseases of the retina is also integrated into this Review. Key experiments that have led to the theories covered are highlighted throughout, as are the knowledge gaps that remain unresolved.

11.
Invest Ophthalmol Vis Sci ; 59(2): 662-673, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29392311

RESUMO

Purpose: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. Methods: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. Results: Aged Cfh+/- mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. Conclusions: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/-∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies.


Assuntos
Anticorpos Bloqueadores/uso terapêutico , Neovascularização de Coroide/terapia , Complemento C5a/antagonistas & inibidores , Modelos Animais de Doenças , Atrofia Geográfica/terapia , Imunoterapia , Animais , Colesterol na Dieta/administração & dosagem , Neovascularização de Coroide/imunologia , Neovascularização de Coroide/patologia , Ativação do Complemento , Complemento C5a/imunologia , Eletrorretinografia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Atrofia Geográfica/imunologia , Atrofia Geográfica/patologia , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Epitélio Pigmentado da Retina/patologia
12.
Hum Gene Ther ; 29(4): 467-479, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28990426

RESUMO

Corneal transplantation (keratoplasty) is the most common type of tissue replacement in the world. The increased rate of graft rejection after keratoplasty is a central problem for repeated transplantations and in inflamed host corneas. It has been shown that apoptosis of grafted epithelium has a role in corneal allograft rejection. This study focused on the T-cell response triggered in BALB/c mice after allogeneic corneal transplantation with and without anti-apoptotic p35-transduced epithelium. To restrict p35 expression to the epithelial cells, modified allogeneic composite grafts were created. As a result, it was found that the proportion of alloreactive CD4+ T cells in postoperatively removed cervical lymph nodes was reduced in the p35-transduced group compared to the allogeneic control group. Diminished priming of the CD4+ T cells was supported by significantly decreased proliferation and lower interferon gamma secretion when compared to allogeneic engraftments. The reduced priming of CD4+ lymphocytes is the first confirmation of the functionality of p35 in the epithelium of corneal grafts to alter the development of the recipient's immune response. Thus, modification of allosensibilization seems to be a promising tool for reducing graft-mediated immune response following corneal transplantation.

13.
EBioMedicine ; 22: 181-190, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28774737

RESUMO

Diabetic retinopathy (DR) is a complication secondary to diabetes and is the number one cause of blindness among working age individuals worldwide. Despite recent therapeutic breakthroughs using pharmacotherapy, a cure for DR has yet to be realized. Several clinical trials have highlighted the vital role dyslipidemia plays in the progression of DR. Additionally, it has recently been shown that activation of Liver X receptor (LXRα/LXRß) prevents DR in diabetic animal models. LXRs are nuclear receptors that play key roles in regulating cholesterol metabolism, fatty acid metabolism and inflammation. In this manuscript, we show insight into DR pathogenesis by demonstrating an innovative signaling axis that unifies key metabolic regulators, Sirtuin 1 and LXR, in modulating retinal cholesterol metabolism and inflammation in the diabetic retina. Expression of both regulators, Sirtuin 1 and LXR, are significantly decreased in diabetic human retinal samples and in a type 2 diabetic animal model. Additionally, activation of LXR restores reverse cholesterol transport, prevents inflammation, reduces pro-inflammatory macrophages activity and prevents the formation of diabetes-induced acellular capillaries. Taken together, the work presented in this manuscript highlights the important role lipid dysregulation plays in DR progression and offers a novel potential therapeutic target for the treatment of DR.


Assuntos
Colesterol/metabolismo , Retinopatia Diabética/metabolismo , Receptores X do Fígado/metabolismo , Sirtuína 1/metabolismo , Animais , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Humanos , Camundongos , Retina/metabolismo , Transdução de Sinais
14.
Immunity ; 47(1): 6-8, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723553

RESUMO

"Paucibacterial" levels of the normal eye surface have left immunologists wondering whether a true microbiome exists there. In this issue of Immunity, St. Leger et al. (2017) address this head-on, discovering a naturally existing commensal in mice that induces γδT cell-mediated protection from opportunistic infection.


Assuntos
Imunidade , Microbiota , Animais , Camundongos
16.
Nat Rev Immunol ; 17(5): 322-332, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28345586

RESUMO

Major advances in mononuclear phagocyte biology have been made but key questions pertinent to their roles in health and disease remain, including in the visual system. One problem concerns how dendritic cells can trigger immune responses from certain tightly regulated immune- privileged sites of the eye. Another, albeit separate, problem involves whether there are functional specializations for microglia versus monocytes in retinal neurodegeneration. In this Review, we examine novel insights in eye immune privilege and, separately, we discuss recent inroads concerning retinal degeneration. Both themes have been extensively studied in the visual system and show parallels with recent findings concerning mononuclear phagocytes in the central nervous system and in the periphery.


Assuntos
Olho/imunologia , Sistema Fagocitário Mononuclear/imunologia , Animais , Olho/citologia , Humanos , Retina/citologia , Retina/imunologia , Percepção Visual
17.
JCI Insight ; 1(12): e87001, 2016 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-27699226

RESUMO

Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.


Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Cicatriz/prevenção & controle , Dissulfiram/farmacologia , Membrana Mucosa/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células Cultivadas , Túnica Conjuntiva/efeitos dos fármacos , Túnica Conjuntiva/fisiopatologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Penfigoide Mucomembranoso Benigno , Tretinoína
18.
JCI Insight ; 1(12)2016 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-27595139

RESUMO

Fibrosis is a shared end-stage pathway to lung, liver, and heart failure. In the ocular mucosa (conjunctiva), fibrosis leads to blindness in trachoma, pemphigoid, and allergy. The indirect fibrogenic role of DCs via T cell activation and inflammatory cell recruitment is well documented. However, here we demonstrate that DCs can directly induce fibrosis. In the mouse model of allergic eye disease (AED), classical CD11b+ DCs in the ocular mucosa showed increased activity of aldehyde dehydrogenase (ALDH), the enzyme required for retinoic acid synthesis. In vitro, CD11b+ DC-derived ALDH was associated with 9-cis-retinoic acid ligation to retinoid x receptor (RXR), which induced conjunctival fibroblast activation. In vivo, stimulating RXR led to rapid onset of ocular mucosal fibrosis, whereas inhibiting ALDH activity in DCs or selectively depleting DCs markedly reduced fibrosis. Collectively, these data reveal a profibrotic ALDH-dependent pathway by DCs and uncover a role for DC retinoid metabolism.

19.
Exp Eye Res ; 151: 68-74, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27519152

RESUMO

In vivo imaging permits longitudinal study of ocular disease processes in the same animal over time. Two different in vivo optical imaging modalities - optical coherence tomography (OCT) and fluorescence - provide important structural and cellular data respectively about disease processes. In this Methods in Eye Research article, we describe and demonstrate the combination of these two modalities producing a truly simultaneous OCT and fluorescence imaging system for imaging of fluorescently labeled animal models. This system uses only a single light source to illuminate both modalities, and both share the same field of view. This allows simultaneous acquisition of OCT and fluorescence images, and the benefits of both techniques are realized without incurring increased costs in variability, light exposure, time, and post-processing effort as would occur when the modalities are used separately. We then utilized this system to demonstrate multi-modal imaging in a progression of samples exhibiting both fluorescence and OCT scattering beginning with resolution targets, ex vivo thy1-YFP labeled neurons in mouse eyes, and finally an in vivo longitudinal time course of GFP labeled myeloid cells in a mouse model of ocular allergy.


Assuntos
Córnea/patologia , Doenças da Córnea/diagnóstico , Iluminação/métodos , Microscopia de Fluorescência/métodos , Retina/patologia , Doenças Retinianas/diagnóstico , Tomografia de Coerência Óptica/métodos , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Reprodutibilidade dos Testes
20.
J Mol Med (Berl) ; 94(11): 1255-1265, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27344677

RESUMO

In this study, the role of CX3CR1 in the progression of diabetic retinopathy (DR) was investigated. The retinas of wild-type (WT), CX3CR1 null (CX3CR1gfp/gfp, KO), and heterozygous (CX3CR1+/gfp, Het) mice were compared in the presence and absence of streptozotocin (STZ)-induced diabetes. CX3CR1 deficiency in STZ-KO increased vascular pathology at 4 months of diabetes, as a significant increase in acellular capillaries was observed only in the STZ-KO group. CX3CR1 deficiency and diabetes had similar effects on retinal neurodegeneration measured by an increase in DNA fragmentation. Retinal vascular pathology in STZ-KO mice was associated with increased numbers of monocyte-derived macrophages in the retina. Furthermore, compared to STZ-WT, STZ-KO mice exhibited increased numbers of inflammatory monocytes in the bone marrow and impaired homing of monocytes to the spleen. The induction of retinal IL-10 expression by diabetes was significantly less in KO mice, and when bone marrow-derived macrophages from KO mice were maintained in high glucose, they expressed significantly less IL-10 and more TNF-α in response to LPS stimulation. These findings support that CX3CR1 deficiency accelerates the development of vascular pathology in DR through increased recruitment of proinflammatory myeloid cells that demonstrate reduced expression of anti-inflammatory IL-10. KEY MESSAGES: • CX3CR1 deletion in STZ-diabetic mice accelerated the onset of diabetic retinopathy (DR). • The early onset of DR was associated with increased retinal cell apoptosis. • The early onset of DR was associated with increased recruitment of bone marrow-derived macrophages to the retina. • Bone marrow-derived macrophages from CX3CR1 KO diabetic mice expressed more TNF-α and less IL-10. • The role of IL-10 in protection from progression of DR is highlighted.


Assuntos
Receptor 1 de Quimiocina CX3C/deficiência , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Animais , Apoptose , Peso Corporal , Células da Medula Óssea/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Modelos Animais de Doenças , Deleção de Genes , Hemoglobina A Glicada/metabolismo , Homeostase , Hipotálamo/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Células Mieloides/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Retina/metabolismo , Retina/patologia , Estreptozocina
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