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Dual-wavelength digital holography effectively expands the measurement range of digital holography, but it increases the complexity of optical system due to non-common-path of two wavelengths. Here, by using orthogonal polarization strategy, we present a dual-wavelength digital holography based on a Wollaston prism (DWDH-WP) to separate the reference beams of two wavelengths and realize the common-path of two wavelengths. A Wollaston prism is inset into the reference beam path of the off-axis digital holography system, so two orthogonal-polarized reference beams of two different wavelengths separated at different directions are generated. Then a dual-wavelength multiplexed interferogram with orthogonal interference fringes is captured by using a monochrome camera, in which both the polarization orientations and the interference fringe orientations of two wavelengths are orthogonal, so the spectral crosstalk of two wavelengths with arbitrary wavelength difference can be avoided. Compared with the existing DWDH method, the proposed DWDH-WP method can conveniently realize the common-path of the reference beams of two wavelengths, so it reveals obvious advantages in spectral separation, spectral crosstalk, system simplification, and adjustment flexibility. Both effectiveness and flexibility of the proposed DWDH-WP method are demonstrated by the phase measurement of the HeLa cell and vortex phase plate.
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BACKGROUND AND PURPOSE: Late secondary glaucoma is an often-severe complication after acute events like anterior segment surgery, trauma and infection. TNF-α is a major mediator that is rapidly upregulated, diffusing also to the retina and causes apoptosis of the ganglion cells and degeneration of their optic nerve axons (mediating steps to glaucomatous damage). Anti-TNF-α antibodies are in animals very effective in protecting the retinal cells and the optic nerve-and might therefore be useful prophylactically against secondary glaucoma in future such patients. Here we evaluate (1) toxicity and (2) efficacy of two TNF-α inhibitors (adalimumab and infliximab), in rabbits by subconjunctival administration. METHODS: For drug toxicity, animals with normal, unburned corneas were injected with adalimumab (0.4, 4, or 40 mg), or infliximab (1, 10, or 100 mg). For drug efficacy, other animals were subjected to alkali burn before such injection, or steroids (for control). The rabbits were evaluated clinically with slit lamp and photography, electroretinography, optical coherence tomography, and intraocular pressure manometry. A sub-set of eyes were stained ex vivo after 3 days for retinal cell apoptosis (TUNEL). In other experiments the optic nerves were evaluated by paraphenylenediamine staining after 50 or 90 days. Loss of retinal cells and optic nerve degeneration were quantified. RESULTS: Subconjunctival administration of 0.4 mg or 4.0 mg adalimumab were well tolerated, whereas 40.0 mg was toxic to the retina. 1, 10, or 100 mg infliximab were also well tolerated. Analysis of the optic nerve axons after 50 days confirmed the safety of 4.0 mg adalimumab and of 100 mg infliximab. For efficacy, 4.0 mg adalimumab subconjunctivally in 0.08 mL provided practically full protection against retinal cell apoptosis 3 days following alkali burn, and infliximab 100 mg only slightly less. At 90 days following burn injury, control optic nerves showed about 50% axon loss as compared to 8% in the adalimumab treatment group. CONCLUSIONS: Subconjunctival injection of 4.0 mg adalimumab in rabbits shows no eye toxicity and provides excellent neuroprotection, both short (3 days) and long-term (90 days). Our total. accumulated data from several of our studies, combined with the present paper, suggest that corneal injuries, including surgery, might benefit from routine administration of anti-TNF-α biologics to reduce inflammation and future secondary glaucoma.
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Axônios , Queimaduras Químicas , Córnea , Nervo Óptico , Inibidores do Fator de Necrose Tumoral , Animais , Coelhos , Adalimumab/uso terapêutico , Apoptose , Queimaduras Químicas/tratamento farmacológico , Modelos Animais de Doenças , Glaucoma , Infliximab/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfaRESUMO
Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a specific method for microglia depletion. However, recent work revealed that in addition to microglia, CSF1R inhibition also affects other innate immune cells, such as peripheral monocytes and tissue-resident macrophages of the lung, liver, spleen, and peritoneum. Here, we show that this effect is not restricted to innate immune cells only but extends to the adaptive immune compartment. CSF1R inhibition alters the transcriptional profile of bone marrow cells that control T helper cell activation. In vivo or ex vivo inhibition of CSF1R profoundly changes the transcriptional profile of CD4+ cells and suppresses Th1 and Th2 differentiation in directionally stimulated and unstimulated cells and independently of microglia depletion. Given that T cells also contribute in CNS pathology, these effects may have practical implications in the interpretation of relevant experimental data.
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Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs. In particular, pH elevation in the anterior chamber (AC) causes acute uveal stress, the release of inflammatory cytokines at the basal limbal tissue, and subsequent LSC damage and death. Peripheral C-C chemokine receptor type 2 positive/CX3C motif chemokine receptor 1 negative (CCR2+ CX3CR1-) monocytes are the key mediators of LSC damage through the upregulation of tumor necrosis factor-alpha (TNF-α) at the limbus. In contrast to peripherally derived monocytes, CX3CR1+ CCR2- tissue-resident macrophages have a protective role, and their depletion prior to injury exacerbates LSC loss and increases LSC vulnerability to TNF-α-mediated apoptosis independently of CCR2+ cell infiltration into the tissue. Consistently, repopulation of the tissue by new resident macrophages not only restores the protective M2-like phenotype of macrophages but also suppresses LSC loss after exposure to inflammatory signals. These findings may have clinical implications in patients with LSC loss after chemical burns or due to other inflammatory conditions.
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Traumatismos Oculares , Deficiência Límbica de Células-Tronco , Humanos , Monócitos , Células-Tronco do Limbo , Fator de Necrose Tumoral alfa , Macrófagos , Receptores de QuimiocinasRESUMO
PURPOSE: This study aimed to develop a clinically feasible and practical therapy for multi-ocular protection following ocular injury by using a thermosensitive drug delivery system (DDS) for sustained delivery of TNF-α and VEGF inhibitors to the eye. METHODS: A thermosensitive, biodegradable hydrogel DDS (PLGA-PEG-PLGA triblock polymer) loaded with 0.7 mg of adalimumab and 1.4 mg of aflibercept was injected subconjunctivally into Dutch-belted pigmented rabbits after corneal alkali injury. Control rabbits received 2 mg of IgG-loaded DDS or 1.4 mg of aflibercept-loaded DDS. Animals were followed for 3 months and assessed for tolerability and prevention of corneal neovascularization (NV), improvement of corneal re-epithelialization, inhibition of retinal ganglion cell (RGC) and optic nerve axon loss, and inhibition of immune cell infiltration into the cornea. Drug-release kinetics was assessed in vivo using an aqueous humor protein analysis. RESULTS: A single subconjunctival administration of dual anti-TNF-α/anti-VEGF DDS achieved a sustained 3-month delivery of antibodies to the anterior chamber, iris, ciliary body, and retina. Administration after corneal alkali burn suppressed CD45+ immune cell infiltration into the cornea, completely inhibited cornea NV for 3 months, accelerated corneal re-epithelialization and wound healing, and prevented RGC and optic nerve axon loss at 3 months. In contrast, anti-VEGF alone or IgG DDS treatment led to persistent corneal epithelial defect (combined: <1%; anti-VEGF: 15%; IgG: 10%, of cornea area), increased infiltration of CD45+ immune cells into the cornea (combined: 28 ± 20; anti-VEGF: 730 ± 178; anti-IgG: 360 ± 186, cells/section), and significant loss of RGCs (combined: 2.7%; anti-VEGF: 63%; IgG: 45%) and optic nerve axons at 3 months. The aqueous humor protein analysis showed first-order release kinetics without adverse effects at the injection site. CONCLUSIONS: Concomitant inhibition of TNF-α and VEGF prevents corneal neovascularization and ameliorates subsequent irreversible damage to the retina and optic nerve after severe ocular injury. A single subconjunctival administration of this therapy, using a biodegradable, slow-release thermosensitive DDS, achieved the sustained elution of therapeutic levels of antibodies to all ocular tissues for 3 months. This therapeutic approach has the potential to dramatically improve the outcomes of severe ocular injuries in patients and improve the therapeutic outcomes in patients with retinal vascular diseases.
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Photocatalytic hydrogen evolution efficiency is limited due to unfavorable carrier dynamics and thermodynamic performance. Here, we propose to introduce electronegative molecules to build an electric double layer (EDL) to generate a polarization field instead of the traditional built-in electric field to improve carrier dynamics, and optimize the thermodynamics by regulating the chemical coordination of surface atoms. Based on theoretical simulation, we designed CuNi@EDL and applied it as the cocatalyst of semiconductor photocatalysts, finally achieved a hydrogen evolution rate of 249.6 mmol h-1 g-1 and remained stable after storing under environmental conditions for more than 300 days. The high H2 yield is mainly due to the perfect work function, Fermi level and Gibbs free energy of hydrogen adsorption, improved light absorption ability, enhanced electron transfer dynamics, decreased HER overpotential and effective carrier transfer channel arose by EDL. Here, our work opens up new perspectives for the design and optimization of photosystems.
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Eletricidade , Excipientes , Adsorção , Simulação por Computador , Hidrogênio , TermodinâmicaRESUMO
Learning-based phase imaging balances high fidelity and speed. However, supervised training requires unmistakable and large-scale datasets, which are often hard or impossible to obtain. Here, we propose an architecture for real-time phase imaging based on physics-enhanced network and equivariance (PEPI). The measurement consistency and equivariant consistency of physical diffraction images are used to optimize the network parameters and invert the process from a single diffraction pattern. In addition, we propose a regularization method based total variation kernel (TV-K) function constraint to output more texture details and high-frequency information. The results show that PEPI can produce the object phase quickly and accurately, and the proposed learning strategy performs closely to the fully supervised method in the evaluation function. Moreover, the PEPI solution can handle high-frequency details better than the fully supervised method. The reconstruction results validate the robustness and generalization ability of the proposed method. Specially, our results show that PEPI leads to considerable performance improvement on the imaging inverse problem, thereby paving the way for high-precision unsupervised phase imaging.
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The perfect optical vortex (POV) beam carrying orbital angular momentum with topological charge-independent radial intensity distribution possesses ubiquitous applications in optical communication, particle manipulation, and quantum optics. But the mode distribution of conventional POV beam is relatively single, limiting the modulation of the particles. Here, we originally introduce the high-order cross-phase (HOCP) and ellipticity γ into the POV beam and construct all-dielectric geometric metasurfaces to generate irregular polygonal perfect optical vortex (IPPOV) beams following the trend of miniaturization and integration of optical systems. By controlling the order of the HOCP, conversion rate u, and ellipticity factor γ, various shapes of IPPOV beams with different electric field intensity distributions can be realized. In addition, we analyze the propagation characteristics of IPPOV beams in free-space, and the number and rotation direction of bright spots at the focal plane give the magnitude and sign of the topological charge carried by the beam. The method does not require cumbersome devices or complex calculation process, and provides a simple and effective method for simultaneous polygon shaping and topological charge measurement. This work further improves the beam manipulation ability while maintaining the characteristics of the POV beam, enriches the mode distribution of the POV beam, and provides more possibilities for particle manipulation.
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The perfect vortex (PV) beam, characterized by carrying orbital angular momentum and a radial electric intensity distribution independent of the topological charge, has important applications in optical communication, particle manipulation, and quantum optics. Conventional methods of generating PV beams require a series of bulky optical elements that are tightly collimated with each other, adding to the complexity of optical systems. Here, making the amplitude of transmitted co-polarized and cross-polarized components to be constant, all-dielectric transmission metasurfaces with superimposed phase profiles integrating spiral phase plate, axicon and Fourier lens are constructed based on the phase-only modulation method. Using mathematical derivation and numerical simulation, multi-channel PV beams with controllable annular ring radius and topological charge are realized for the first time under circularly polarized light incidence combining the propagation phase and geometric phase. Meanwhile, perfect vector vortex beams are produced by superposition of PV beams under the incidence of left-handed circularly polarized and right-handed circularly polarized lights, respectively. This work provides a new perspective on generating tailored PV beams, increasing design flexibility and facilitating the construction of compact, integrated, and versatile nanophotonics platforms.
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Based on synchronous phase shift determination, we propose a differential phase measurement method for differential interference contrast (DIC) microscopy. An on-line phase shift measurement device is used to generate carrier interferograms and determine the phase shift of DIC images. Then the differential phase can be extracted with the least-squares phase-shifting algorithm. In addition to realizing on-line, dynamic, real-time, synchronous and high precision phase shift measurement, the proposed method also can reconstruct the phase of the specimen by using the phase-integral algorithm. The differential phase measurement method reveals obvious advantages in error compensation, anti-interference, and noise suppression. Both simulation analysis and experimental result demonstrate that using the proposed method, the accuracy of phase shift measurement is higher than 0.007 rad. Very accurate phase reconstructions were obtained with both polystyrene microspheres and human vascular endothelial.
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Algoritmos , Simulação por Computador , HumanosRESUMO
The optical vortex (OV) beams characterized by orbital angular momentum (OAM) possess ubiquitous applications in optical communication and nanoparticle manipulation. Particularly, the vortex vector beams are important in classical physics and quantum sciences. Here, based on an all-dielectric transmission metasurface platform, we demonstrate a spin-multiplexed metadevice combining propagation phase and Pancharatnam-Berry (PB) phase. By utilizing a phase-only modulation method, the metadevice can generate spin-dependent and multidimensional focused optical vortex (FOV) under the orthogonally circularly polarized incident light, and it can successfully realize the multiplexed of the above-mentioned FOVs for linearly polarized light. Meanwhile, the superposition of multiple OAM states can also produce vector vortex beams with different modes. Additionally, the evolution process of the electric field intensity profile is presented after the resultant vector vortex beams through a horizontal linear polarization. This work paves an innovative way for generating structured beams, and it provides promising opportunities for advanced applications in optical data storage, optical micromanipulation, and data communication.
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Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1ß, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.
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Hematopoese/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/imunologia , Feminino , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fagocitose/efeitos dos fármacos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Especificidade da EspécieRESUMO
Purpose: To describe a novel microporous drug delivery system (DDS) for sustained anti- vascular endothelial growth factor (VEGF) delivery to the eye and to evaluate its efficacy in a corneal injury model. Methods: A macro-porous DDS (1.5 × 1.5 × 4 mm) loaded with 2 mg of bevacizumab was implanted subconjunctivally in three Dutch-belted pigmented rabbits after corneal alkali injury (2N NaOH). Three rabbits received sham DDS. Animals were followed for three months and assessed in vivo and ex vivo for corneal neovascularization (NV), epithelial defect, stromal scarring, endothelial cell loss, and expression of angiogenic and inflammatory markers in the cornea and retina. Results: Anti-VEGF DDS treatment led to complete inhibition of superior cornea NV and complete corneal re-epithelialization by day 58 whereas sham DDS resulted in severe cornea NV and persistent epithelial defect (9%â¼12% of total cornea area) through the end of the study. Histologically, anti-VEGF DDS significantly reduced CD45+ and F4/80 CD11b+ cell accumulation (79%, P < 0.05) in the cornea, ameliorated tumor necrosis factor-α expression (90%, P < 0.05), reduced corneal stromal scarring and prevented corneal endothelial cell loss, as compared to sham DDS. Moreover, anti-VEGF DDS achieved retinal penetration and reduction in retinal VEGF levels at 3 months. Conclusions: Use of subconjunctival anti-VEGF DDS suppresses cornea NV, inflammation, stromal scarring, prevents endothelial cell loss, and abrogates retinal VEGF upregulation in a rabbit corneal alkali burn model. Moreover, it delivers anti-VEGF antibodies to the retina for three months. This delivery platform could enable antibody therapy of other corneal and retinal vascular pathologies. Translational Relevance: We describe a method for sustained anti-VEGF delivery to the eye for the treatment of ocular injuries.
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Neovascularização da Córnea , Queimaduras Oculares , Animais , Neovascularização da Córnea/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Coelhos , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Fatores de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
The Co3O4@CdS double-layered hollow spheres were first prepared by the template-removal method with the assistance of the ZIF-67 material; the structure has been proved by transmission electron microscopy (TEM). The Co3O4@CdS hollow spheres calcinated at 400 °C exhibited the highest photodegradation activity. Nearly 90% phenol was degraded after 2 h of visible-light irradiation. More than 80% rhodamine-B (RhB) was degraded within the first 30 min and nearly eliminated after 1 h of irradiation. The mechanism of the photodegradation reaction was investigated. Based on the analysis of electron spin resonance (ESR) spectra and radical trapping test, it was found that superoxide radicals are the major oxidative species for dye degradation and holes and hydroxyl radicals are the major oxidative species for phenol degradation. These results may be used in industrial wastewater treatment. The reaction obeys first-order reaction kinetics, and the rate constant of the Co3O4@CdS hollow sphere in dye degradation is 0.05 min-1 and that in phenol degradation is 0.02 min-1, which is three times higher than that of CdS nanoparticles. These results indicated the high oxidizing ability of the samples.
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Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, and infection. Postevent inflammation and neuroglial remodeling play a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using three different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques, we show that ocular trauma or surgery can cause robust infiltration of bone marrow-derived monocytes into the retina and subsequent neuroinflammation by up-regulation of Tnf, Il1b, and Il6 mRNA within 24 hours. This is accompanied by ganglion cell apoptosis and neurodegeneration. Prompt inhibition of tumor necrosis factor-α or IL-1ß markedly suppresses monocyte infiltration and ganglion cell loss. Thus, acute ocular injury (surgical or trauma) can lead to rapid neuroretinal inflammation and subsequent ganglion cell loss, the hallmark of glaucoma. Infiltrating monocytes play a central role in this process, likely amplifying the inflammatory cascade, aiding in the activation of retinal microglia. Prompt administration of cytokine inhibitors after ocular injury prevents this infiltration and ameliorates the damage to the retina-suggesting that it may be used prophylactically for neuroprotection against post-traumatic glaucoma.
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Citocinas/antagonistas & inibidores , Glaucoma/metabolismo , Monócitos/patologia , Neuroglia/patologia , Retina/cirurgia , Animais , Queimaduras Químicas/metabolismo , Queimaduras Químicas/patologia , Córnea/metabolismo , Córnea/patologia , Modelos Animais de Doenças , Glaucoma/patologia , Camundongos Transgênicos , Monócitos/metabolismo , Retina/metabolismoRESUMO
Artificial cornea is an effective treatment of corneal blindness. Yet, intraocular pressure (IOP) measurements for glaucoma monitoring remain an urgent unmet need. Here, we present the integration of a fiber-optic Fabry-Perot pressure sensor with an FDA-approved keratoprosthesis for real-time IOP measurements using a novel strategy based on optical-path self-alignment with micromagnets. Additionally, an alternative noncontact sensor-interrogation approach is demonstrated using a bench-top optical coherence tomography system. We show stable pressure readings with low baseline drift (<2.8 mm Hg) for >4.5 years in vitro and efficacy in IOP interrogation in vivo using fiber-optic self-alignment, with good initial agreement with the actual IOP. Subsequently, IOP drift in vivo was due to retroprosthetic membrane (RPM) formation on the sensor secondary to surgical inflammation (more severe in the current pro-fibrotic rabbit model). This study paves the way for clinical adaptation of optical pressure sensors with ocular implants, highlighting the importance of controlling RPM in clinical adaptation.
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Córnea , Doenças da Córnea , Animais , Pressão Intraocular , Próteses e Implantes , Coelhos , Tomografia de Coerência Óptica , Tonometria OcularRESUMO
PURPOSE: To review clinical aspects and cellular and molecular steps in the development of long-term glaucoma after corneal surgery or acute trauma-especially the pivotal role of tumor necrosis factor alpha (TNF-α), the rapidity of the secondary damage to the retinal ganglion cells, and the clinical promise of early antiinflammatory intervention. METHODS: A series of laboratory studies on post-injury and post-surgery glaucoma have been compared to clinical outcome studies on the subject, focusing particularly on the vulnerability of the retinal ganglion cells. Alkali burn to the cornea of mice and rabbits served as the main experimental model. TNF-α titer, ganglion cell apoptosis, and depletion of optic nerve axons have been examined. Anti-TNF-α antibodies or corticosteroids have been used to protect the retinal ganglion cells. Intraocular pressure (IOP) postburn was recorded by manometric methods. RESULTS: In animals with alkali burn to the cornea, damage to the retina can occur within 24 to 72 hours. This is not because of a direct pH change posteriorly-the alkali is effectively buffered at the iris-lens level. Rather, TNF-α (and other inflammatory cytokines), generated anteriorly, rapidly diffuses posteriorly to cause apoptosis of the ganglion cells. During this time, the IOP remains much lower than the reported values required to cause ganglion cell damage. The TNF-α antibody infliximab or corticosteroids, if administered promptly, are markedly protective of the ganglion cells. CONCLUSIONS: A rapidly initiated, inflammatory (TNF-α mediated), IOP-independent pathway to glaucoma, resulting from acute anterior segment trauma or surgery, has been identified in laboratory studies. Prompt prophylactic treatment with antiinflammatory agents has been shown to be markedly neuroprotective of retinal ganglion cells, presumably capable of reducing the risk of late glaucoma.
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Doenças da Córnea/cirurgia , Lesões da Córnea/complicações , Glaucoma/etiologia , Pressão Intraocular/fisiologia , Procedimentos Cirúrgicos Refrativos/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo , Animais , Queimaduras Químicas/etiologia , Queimaduras Químicas/metabolismo , Doenças da Córnea/metabolismo , Lesões da Córnea/metabolismo , Queimaduras Oculares/induzido quimicamente , Queimaduras Oculares/metabolismo , Glaucoma/metabolismo , Camundongos , Coelhos , Células Ganglionares da Retina/metabolismo , Tonometria OcularRESUMO
Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and CNS. However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a proinflammatory phenotype that promotes neurodegeneration. In this study, we show that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as Il17f, Tnfsf11, Ccl4, Il1a, Ccr2, Il4, Il5, and Csf2 in the retina, and abnormal engraftment of peripheral CCR2+ CX3CR1+ monocytes into the retina, which is associated with increased retinal ganglion cell loss, retinal nerve fiber layer thinning, and pigmentation onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension also cause similar changes. However, optic nerve crush injury-mediated retinal ganglion cell loss evokes neither peripheral monocyte response in the retina nor pigmentation, although peripheral CX3CR1+ and CCR2+ monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and retinal pigment epithelium migration, and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.
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Córnea/fisiologia , Traumatismos Oculares/imunologia , Microglia/fisiologia , Monócitos/fisiologia , Doenças Neurodegenerativas/imunologia , Neuroglia/fisiologia , Traumatismos do Nervo Óptico/imunologia , Retina/fisiologia , Degeneração Retiniana/imunologia , Animais , Movimento Celular , Córnea/patologia , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Modelos Animais , Plasticidade Neuronal , Retina/patologiaRESUMO
Previous studies have demonstrated that ocular injury can lead to prompt infiltration of bone-marrow-derived peripheral monocytes into the retina. However, the ability of these cells to integrate into the tissue and become microglia has not been investigated. Here we show that such peripheral monocytes that infiltrate into the retina after ocular injury engraft permanently, migrate to the three distinct microglia strata, and adopt a microglia-like morphology. In the absence of ocular injury, peripheral monocytes that repopulate the retina after depletion with colony-stimulating factor 1 receptor (CSF1R) inhibitor remain sensitive to CSF1R inhibition and can be redepleted. Strikingly, consequent to ocular injury, the engrafted peripheral monocytes are resistant to depletion by CSF1R inhibitor and likely express low CSF1R. Moreover, these engrafted monocytes remain proinflammatory, expressing high levels of MHC-II, IL-1ß, and TNF-α over the long term. The observed permanent neuroglia remodeling after injury constitutes a major immunological change that may contribute to progressive retinal degeneration. These findings may also be relevant to other degenerative conditions of the retina and the central nervous system.