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    AIM2 deletion enhances blood-brain barrier integrity in experimental ischemic stroke. Xu Si-Yi,Bian Hui-Jie,Shu Shu,Xia Sheng-Nan,Gu Yue,Zhang Mei-Juan,Xu Yun,Cao Xiang CNS neuroscience & therapeutics AIMS:Ischemic stroke is a life-threatening disease with limited therapeutic strategies. Blood-brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown. METHODS:Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins. RESULTS:AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM-1 and decreased those of the tight junction (TJ) proteins ZO-1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM-1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R-induced increases in ICAM-1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p-STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown. CONCLUSION:Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke. 10.1111/cns.13699
    Melatonin Maintains Inner Blood-Retinal Barrier by Regulating Microglia Inhibition of PI3K/Akt/Stat3/NF-κB Signaling Pathways in Experimental Diabetic Retinopathy. Frontiers in immunology Microglial activation and melatonin protection have been reported in diabetic retinopathy (DR). Whether melatonin could regulate microglia to protect the inner blood-retinal barrier (iBRB) remains unknown. In this study, the role of microglia in iBRB breakdown and the mechanisms of melatonin's regulation on microglia were explored. In diabetic rat retinas, activated microglia proliferated and migrated from the inner retina to the outer retina, accompanied by the obvious morphological changes. Meanwhile, significant leakage of albumin was evidenced at the site of close interaction between activated microglia and the damaged pericytes and endothelial cells. , inflammation-related cytokines, such as tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and arginase-1 (Arg-1), were increased significantly in CoCl-treated BV2 cells. The supernatant derived from CoCl-treated BV2 cells significantly decreased the cell viability and disrupted the junctional proteins in both pericytes and endothelial cells, resulting in severe leakage. Melatonin suppressed the microglial overactivation, i.e., decreasing the cell number and promoting its anti-inflammatory properties in diabetic rat retinas. Moreover, the leakage of iBRB was alleviated and the pericyte coverage was restored after melatonin treatment. , when treated with melatonin in CoCl-treated BV2 cells, the inflammatory factors were decreased, while the anti-inflammatory factors were increased, further reducing the pericyte loss and increasing the tight junctions. Melatonin deactivated microglia inhibition of PI3K/Akt/Stat3/NF-κB signaling pathways, thus maintaining the integrity of iBRB. The present data support a causal role for activated microglia in iBRB breakdown and highlight the therapeutic potential of melatonin in the treatment of DR by regulating microglia. 10.3389/fimmu.2022.831660
    Salvianolic acid C improves cerebral ischemia reperfusion injury through suppressing microglial cell M1 polarization and promoting cerebral angiogenesis. International immunopharmacology This study aimed to investigate the mechanism of salvianolic acid C (SAC), the active ingredient in Salvia miltiorrhiza, in improving cerebral ischemia injury. The mouse microglial cells BV2 and mouse endothelial cells bEnd.3 were used as the objects of study. LPS/IFN-γ was applied to simulate the BV2 polarization, and bEnd.3 cells were treated under hypoxic condition. The BV2 cell polarization level was measured through flow cytometry (FCM), the TLR4 and MyD88 expression levels were detected by fluorescence staining, whereas the expression of inflammatory factors TNF-α, IL-6 and IL-1β was analyzed through ELISA. Tubule formation assay was also conducted to observe the tubule formation ability of bEnd.3 cells in vitro, and the level of VEGFR2 was detected by fluorescence staining. Cells were treated with the PKM2 inhibitor IN3, aiming to observe the influence of SAC on glycolysis of BV2 cells. In addition, the mouse model of cerebral ischemia was constructed through the middle cerebral artery occlusion (MCAO) method, and the pathological changes in brain tissues were detected after SAC intervention. Meanwhile, the levels of IBA-1, CD31 and ZO-1 were determined through histochemical staining. Nissl staining to detect nerve cell damage. In BV2 cell experiment, SAC suppressed the M1 polarization of BV2 cells, reduced the inflammatory factor levels, and inhibited the activation of TLR4 signal through suppressing glycolysis. When PKM2 was suppressed, the effects of SAC were antagonized. In the bEnd.3 model, SAC promoted tubule formation in bEnd.3 cells under hypoxic condition, and increased the expression of VEGFR2 and Notch1. In the mouse model, SAC improved the neurological function in MCAO mice, and inhibited the activation of microglial cells and the expression of inflammatory factors. At the same time, SAC up-regulated the expression of ZO-1 and CD31, and maintained the blood-brain barrier (BBB) function. As a major component of Salvia miltiorrhiza, SAC can suppress microglial cell polarization and promote tubule formation in endothelial cells to exert the neurological repair function in cerebral ischemia. SAC is a multi-functional neuroprotective small molecule. 10.1016/j.intimp.2022.109021
    Virus-mediated EpoR76E gene therapy preserves vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress. Hines-Beard Jessica,Bond Wesley S,Backstrom Jon R,Rex Tonia S Journal of neuroinflammation BACKGROUND:Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E. METHODS:Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed. RESULTS:Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice. CONCLUSIONS:Treatment with rAAV.EpoR76E preserves vision in the DBA/2J model of glaucoma at least in part by decreasing infiltration of peripheral immune cells, modulating microglial reactivity, and decreasing oxidative stress. 10.1186/s12974-016-0499-5
    Neuroprotective effect of minocycline in a rat model of branch retinal vein occlusion. Sun Chuan,Li Xiao-Xin,He Xiang-Jun,Zhang Qi,Tao Yong Experimental eye research Branch retinal vein occlusion (BRVO) is the second most frequent retinal vascular disorder. Currently the first-line therapies for BRVO include anti-VEGF and dexamethasone implant treatment, however, with direct or indirect damage on retinal neurons, it has limited effect in improving patients visual acuity. Therefore, novel treatments with neuroprotective effect for BRVO retina were expected. Minocycline is a semisynthetic, broad spectrum tetracycline antibiotic with high penetration through the blood brain barrier. The neuroprotective effects of minocycline have been shown in various central nervous system (CNS) disease. Since both CNS and retina were composed of neurons and glials, it is reasonable to expect a neuroprotective effect by minocycline for BRVO retina. Therefore, the aim of the present study was to study whether minocycline has neuroprotective effect in branch retinal vein occlusion (BRVO) and the possible underlying molecular basis. We created BRVO in rats using laser photocoagulation. The animals were then randomly divided into 4 groups to evaluate the effect of minocycline: group A: minocycline 45 mg/kg intraperitoneal injection (i.p.), group B: minocycline 90 mg/kg i.p., group C: normal saline i.p., group D: sham injection. Fundus photography and fluorescein angiography (FA) were conducted. The changes in thickness of retinal layers were measured with optical coherence tomography (OCT) in vivo. We found that retinal edema occurred predominantly in the inner retinal layers. Intraperitoneal administration of minocycline significantly ameliorated retinal edema in the early stage of BRVO. We performed Full field Electroretinography (ffERG) to evaluate retinal function and found that the reduction of b wave amplitude decreased in the combined maximal response. The expressional levels of apoptosis related genes (Bax, Bcl-2) and inflammation related genes (IL-1 β, TNF α, MCP-1 and CCR2) were measured by real-time PCR, the results showed that minocycline treatment upregulated Bcl-2 expression and inhibits TNF α expression since early stage of BRVO. We also performed Hematoxylin-Eosin (HE) and immunostaining for Iba 1 (a microgilal marker), active caspase-3, Bax, Bcl-2, IL-1 β, TNF α and found that minocycline inhibits retinal microglial activation, prevents retinal ganglion cell loss, and inhibits retinal caspase-3 activation. Thus, our study indicates that systemic administration of minocycline ameliorates retinal edema and preserves retinal function in the early stage of BRVO possibly via inhibiting microglia activation and protecting RGC from apoptosis. 10.1016/j.exer.2013.05.018
    Retinal Phenotype in the rd9 Mutant Mouse, a Model of X-Linked RP. Falasconi Antonio,Biagioni Martina,Novelli Elena,Piano Ilaria,Gargini Claudia,Strettoi Enrica Frontiers in neuroscience Retinal degeneration 9 (rd9) mice carry a mutation in the retina specific "Retinitis Pigmentosa GTPase Regulator (RPGR)" Open Reading Frame (ORF) 15 gene, located on the X chromosome and represent a rare model of X-linked Retinitis Pigmentosa (XLRP), a common and severe form of retinal degeneration (Wright et al., 2010; Tsang and Sharma, 2018). The rd9 RPGR-ORF15 mutation in mice causes lack of the protein in photoreceptors and a slow degeneration of these cells with consequent decrease in Outer Nuclear Layer (ONL) thickness and amplitude of ERG responses, as previously described (Thompson et al., 2012). However, relative rates of rod and cone photoreceptor loss, as well as secondary alterations occurring in neuronal and non-neuronal retinal cell types of rd9 mutants remain to be assessed. Aim of this study is to extend phenotype analysis of the rd9 mouse retina focusing on changes occurring in cells directly interacting with photoreceptors. To this purpose, first we estimated rod and cone survival and its degree of intraretinal variation over time; then, we studied the morphology of horizontal and bipolar cells and of the retinal pigment epithelium (RPE), extending our observations to glial cell reactivity. We found that in rd9 retinas rod (but not cone) death is the main cause of decrease in ONL thickness and that degeneration shows a high degree of intraretinal variation. Rod loss drives remodeling in the outer retina, with sprouting of second-order neurons of the rod-pathway and relative sparing of cone pathway elements. Remarkably, despite cone survival, functional defects can be clearly detected in ERG recordings in both scotopic and photopic conditions. Moderate levels of Muller cells and microglial reactivity are sided by striking attenuation of staining for RPE tight junctions, suggesting altered integrity of the outer Blood Retina Barrier (BRB). Because of many features resembling slowly progressing photoreceptor degeneration paradigms or early stages of more aggressive forms of RP, the rd9 mouse model can be considered a rare and useful tool to investigate retinal changes associated to a process of photoreceptor death sustained throughout life and to reveal disease biomarkers (e.g., BRB alterations) of human XLRP. 10.3389/fnins.2019.00991
    Inosine diphosphatase as a histochemical marker of retinal microvasculature, with special reference to transformation of microglia. Sanyal S,De Ruiter A Cell and tissue research Nucleoside diphosphatase (IDPase), localized using inosine diphosphate as substrate, allows the selective staining of blood vessels and cells of vascular origin, such as macrophages and microglia, whereas the neuroglial, the neuronal and the pigment epithelial cells remain unstained. The staining pattern observed in the retina of mouse, rat, cat and monkey are similar; some apparent quantitative differences reflect species differences in the distribution of retinal microvasculature. At the electron-microscopic level, most of the enzyme activity in the blood vessels appears to be located along the outer wall. The cell membrane, parts of the smooth endoplasmic reticulum and the nuclear membrane in the microglial perikarya appear positive; profiles of microglial processes are intensely stained. In the developing eyes of rats and mice, the blood vessels are stainable from the earliest stage of their appearance. An array of amoeboid cells precede the growing blood vessels and spread out over the future vascularized part of the retina. These cells eventually develop characteristic microglial features, and extend many elongated and branched processes between the neuroepithelial cells while remaining in contact with, or in close proximity to, the blood vessels. Intense IDPase activity in the microglial cells, in contrast to the absence of the enzyme in the neuroglial Müller cells, suggests that microglia are involved in phosphate metabolism and indicates functional compartmentalization within the glial tissue lying between the blood retinal barrier and the retinal neurons. 10.1007/bf00217173
    Reactive changes of retinal microglia during fatal murine cerebral malaria: effects of dexamethasone and experimental permeabilization of the blood-brain barrier. Medana I M,Chan-Ling T,Hunt N H The American journal of pathology Microglial activation and redistribution toward blood vessels are some of the earliest observable events occurring within the central nervous system (CNS) during fatal murine cerebral malaria (FMCM). To investigate stimuli that might modulate microglial reactivity during FMCM we have performed two experimental manipulations and observed microglial responses in retinal whole mounts. First, to determine whether increased blood-brain barrier (BBB) permeability in the absence of the malaria parasite initiates the microglial changes, BBB function was compromised experimentally by intracarotid injection of arabinose and retinae were examined 12, 24, or 36 hours later. Second, to determine whether the immune response against the malaria parasite modulates microglial reactivity, infected mice were treated with dexamethasone before day 4 postinoculation. This treatment regime ameliorates cerebral complications without affecting parasite growth. We observed that increased BBB permeability was sufficient to elicit thickening of microglial processes and redistribution of microglia toward the vasculature, characteristic of the early stages of FMCM. However, despite the presence of plasma constituents in the CNS for up to 36 hours, microglia with amoeboid and vacuolated morphology were not observed. Dexamethasone treatment inhibited the up-regulation of alpha-D-galactose expression and reactive morphological changes in microglia during FMCM. These results suggest that disruption of the CNS milieu by entry of plasma constituents, or circulating malaria parasites in the absence of an immune response, by themselves are insufficient to induce the reactive microglial changes that are characteristic of FMCM. In addition, dexamethasone-sensitive event(s), presumably associated with immune system activation, occurring within the first few days of malaria infection are essential for the development of reactive microglia and subsequent fatal neurological complications. 10.1016/S0002-9440(10)64973-5
    Origin of fundus hyperautofluorescent spots and their role in retinal degeneration in a mouse model of Goldmann-Favre syndrome. Wang Nan-Kai,Lai Chi-Chun,Liu Chi-Hsiu,Yeh Lung-Kun,Chou Chai Lin,Kong Jian,Nagasaki Takayuki,Tsang Stephen H,Chien Chung-Liang Disease models & mechanisms Goldmann-Favre syndrome, also known as enhanced S-cone syndrome, is an inherited retinal degeneration disease in which a gain of photoreceptor cell types results in retinal dysplasia and degeneration. Although microglia have been implicated in the pathogenesis of many neurodegenerative diseases, the fundamental role of these cells in this disease is unknown. In the current study, sequential analyses suggest that microglia are recruited and appear after outer nuclear layer folding. By crossing rd7 mice (a model for hereditary retinal degeneration owing to Nr2e3 mutation) with mice carrying the macrophage Fas-induced apoptosis (Mafia) transgene, we generated double-mutant mice and studied the role of the resident retinal microglia. Microglial cells in these double-mutant mice express enhanced green fluorescent protein (EGFP) and a suicide gene that can trigger Fas-mediated apoptosis via systemic treatment with AP20187 (FK506 dimerizer). We demonstrated that more than 80% of the EGFP+ cells in retinas from rd7/rd7;Tg/Tg mice express Iba-1 (a microglial marker), and resident microglia are still present in the retina because AP20187 does not cross the blood-brain barrier. Hence, only circulating bone marrow (BM)-derived microglia are depleted. Depletion of circulating BM-derived microglia accelerates retinal degeneration in rd7 mice. An increased number of autofluorescent (AF) spots is a consequence of resident microglia proliferation, which in turn establishes an inflammatory cytokine milieu via the upregulation of IL-1β, IL-6 and TNFα expression. This inflammation is likely to accelerate retinal degeneration. This study not only identifies inflammation as a crucial step in the pathogenesis of retinal degeneration, but also highlights the involvement of specific cytokine genes that could serve as future treatment targets in retinal degenerations. 10.1242/dmm.012112
    Generation of activated sialoadhesin-positive microglia during retinal degeneration. Hughes Edward H,Schlichtenbrede Frank C,Murphy Conor C,Sarra Gian-Marco,Luthert Philip J,Ali Robin R,Dick Andrew D Investigative ophthalmology & visual science PURPOSE:The retina contains a rich network of myeloid-derived cells (microglia) within the retinal parenchyma and surrounding vessels. Their response and behavior during inflammation and neurodegeneration remain largely undefined. In the present study, the behavior of microglia was closely examined during the onset of photoreceptor degeneration in the rds mouse, to assess their role in photoreceptor apoptosis. The results may have relevance to similar degeneration in humans (retinitis pigmentosa). METHODS:Retinas from rds and wild-type CBA mice aged 8, 14, 16, 17, 19, 21, 30, and 40 days were examined immunohistochemically, with antibodies to macrophage cell surface markers, inducible nitric oxide synthase (iNOS), and proliferating cell nuclear antigen (PCNA), during the most active phase of the disease. TUNEL was used to assess photoreceptor apoptosis. RESULTS:In the rds mouse, microglia proliferated in situ (PCNA), migrated to the subretinal space, and adopted an activated phenotype. Maximum microglial cells occurred at postnatal day (P)21, 5 days after the peak in photoreceptor apoptosis (P16). Microglia did not express iNOS, and nitrotyrosine was absent. Sialoadhesin was expressed on microglia from P14, and expression was greatest at P21. CONCLUSIONS:During retinal degeneration, microglia are activated and express sialoadhesin. The temporal relationship between photoreceptor apoptosis and microglial response suggests that microglia are not responsible for the initial wave of photoreceptor death, and this is corroborated by the absence of iNOS and nitrotyrosine. Expression of sialoadhesin may indicate blood-retinal barrier breakdown, which has immune implications for subretinal gene therapeutic strategies. 10.1167/iovs.02-0824
    Microglia-targeted pharmacotherapy in retinal neurodegenerative diseases. Schuetz Erik,Thanos Solon Current drug targets Microglial cells, members of the monocytic lineage, represent the resident immunocompetent cells of the central nervous system including the retina with its peculiarities like a double blood retinal barrier. Microglial cells invade the retina in response to naturally occurring neuronal death during embryonic development and remodelling. Resident microglial cells are extremely sensitive to changes in their microenvironment arising from either traumatic or chronic neurodegeneration, inproper wiring, hereditary diseases or infection and become rapidly activated. In their activated state, the cells undergo drastic morphological changes, upregulate a variety of receptors and secrete soluble factors, which contribute to recognition and phagocytotic cleareance of dying or malfunctioning neurons. In this review, we aim to summarise the current knowledge of microglial involvement in experimentally induced or naturally occurring retinal neurodegenerations with emphasising on mechanisms of microglia activation. Expanding on the mechanisms, we shall discuss on approaches to pharmacologically interfere with the microglial activation and neurophagy. The protagonistic role of these cells in the outcome of certain diseases may help designing microglial targeted treatments with potential benefit for neuronal survival and regeneration in clinically relevant conditions.
    Embryonic Pericytes Promote Microglial Homeostasis and Their Effects on Neural Progenitors in the Developing Cerebral Cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience Multifaceted microglial functions in the developing brain, such as promoting the differentiation of neural progenitors and contributing to the positioning and survival of neurons, have been progressively revealed. Although previous studies have noted the relationship between vascular endothelial cells and microglia in the developing brain, little attention has been given to the importance of pericytes, the mural cells surrounding endothelial cells. In this study, we attempted to dissect the role of pericytes in microglial distribution and function in developing mouse brains. Our immunohistochemical analysis showed that approximately half of the microglia attached to capillaries in the cerebral walls. Notably, a magnified observation of the position of microglia, vascular endothelial cells and pericytes demonstrated that microglia were preferentially associated with pericytes that covered 79.8% of the total capillary surface area. Through pericyte depletion induced by the intraventricular administration of a neutralizing antibody against platelet-derived growth factor receptor (PDGFR)β (clone APB5), we found that microglial density was markedly decreased compared with that in control antibody-treated brains because of their low proliferative capacity. Moreover, coculture of isolated CD11b microglia and NG2PDGFRα cells, which are mostly composed of pericytes, from parenchymal cells indicated that pericytes promote microglial proliferation via the production of soluble factors. Furthermore, pericyte depletion by APB5 treatment resulted in a failure of microglia to promote the differentiation of neural stem cells into intermediate progenitors. Taken together, our findings suggest that pericytes facilitate microglial homeostasis in the developing brains, thereby indirectly supporting microglial effects on neural progenitors. This study highlights the novel effect of pericytes on microglia in the developing mouse brain. Through multiple analyses using an pericyte depletion mouse model and an coculture study of isolated pericytes and microglia from parenchymal cells, we demonstrated that pericytes contribute to microglial proliferation and support microglia in efficiently promoting the differentiation of neural stem cells into intermediate progenitors. Our present data provide evidence that pericytes function not only in the maintenance of cerebral microcirculation and blood brain barrier (BBB) integrity but also in microglial homeostasis in the developing cerebral walls. These findings will expand our knowledge and help elucidate the mechanism of brain development both in healthy and disease conditions. 10.1523/JNEUROSCI.1201-21.2021
    Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3 neurodegenerative microglia. Acta neuropathologica communications Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a and Galectin-3 MGnD microglia in retinas of transgenic APP/PS1 AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible Cre system in APP/PS1 mice diminished retinal Clec7a and Galectin-3 microglial populations while increasing homeostatic P2ry12 microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APP/PS1 mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases. 10.1186/s40478-022-01439-z
    Sub-threshold micropulse laser treatment reduces inflammatory biomarkers in aqueous humour of diabetic patients with macular edema. Midena Edoardo,Micera Alessandra,Frizziero Luisa,Pilotto Elisabetta,Esposito Graziana,Bini Silvia Scientific reports Subthreshold micropulse laser (SMPL) is a tissue-sparing technique whose efficacy is demonstrated for diabetic macular edema (DME) treatment. However, its mechanism of action is poorly known. A prospective observational study was performed on naïve DME patients treated with SMPL, to evaluate the changes of aqueous humor (AH) inflammatory and vaso-active biomarkers after treatments. AH samples of eighteen DME eyes were collected before and after SMPL. Ten non-diabetic AH samples served as controls. Full ophthalmic evaluation, spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography were performed in DME group. Glass chip protein array was used to quantify 58 inflammatory molecules. Central retinal thickness (CRT) and visual acuity were also monitored. Several molecules showed different concentrations in DME eyes versus controls (p value < 0.05). Fas Ligand (FasL), Macrophage Inflammatory Proteins (MIP)-1α, Regulated on Activation Normal T Cell Expressed and Secreted (RANTES) and Vascular Endothelial Growth Factor (VEGF) were increased in DME at baseline versus controls and decreased after SMPL treatments (p < 0.05). CRT reduction and visual acuity improvement were also found. Inflammatory cytokines, mainly produced by the retinal microglia, were significantly reduced after treatments, suggesting that SMPL may act by de-activating microglial cells, and reducing local inflammatory diabetes-related response. 10.1038/s41598-019-46515-y
    Para-inflammation in the aging retina. Xu Heping,Chen Mei,Forrester John V Progress in retinal and eye research Para-inflammation is a tissue adaptive response to noxious stress or malfunction and has characteristics that are intermediate between basal and inflammatory states (Medzhitov, 2008). The physiological purpose of para-inflammation is to restore tissue functionality and homeostasis. Para-inflammation may become chronic or turn into inflammation if tissue stress or malfunction persists for a sustained period. Chronic para-inflammation contributes to the initiation and progression of many human diseases including obesity, type 2 diabetes, atherosclerosis, and age-related neurodegenerative diseases. Evidence from our studies and the studies of some others suggests that para-inflammation also exists in the aging retina in physiological conditions and might contribute to age-related retinal pathologies. The purpose of this review is to introduce the notion of "para-inflammation" as a state between frank, overt destructive inflammation and the non-inflammatory removal of dead or dying cells by apoptosis, to the retinal community. In diabetes and atherosclerosis, leukocytes particularly monocytes and vascular endothelial cells are constantly under noxious stress due to glycaemic and/or lipidaemic dysregulation. These blood-borne stresses trigger para-inflammatory responses in leukocytes and endothelial cells by up-regulating the expression of adhesion molecules or releasing cytokines/chemokines, which in turn cause abnormal leukocyte-endothelial interactions and ultimately vascular damage. In the aging retina, on the other hand, oxidized lipoproteins and free radicals are considered to be major causes of tissue stress and serve as local triggers for retinal para-inflammation. Microarray analysis has revealed the up-regulation of a large number of inflammatory genes, including genes involved in complement activation and inflammatory cytokine/chemokine production, in the aging retina. Para-inflammatory responses in the neuroretina of aged mice are characterized by microglial activation and subretinal migration, and breakdown of blood-retinal barrier. At the retinal/choroidal interface para-inflammation is manifested by complement activation in Bruch's membrane and RPE cells, and microglia accumulation in subretinal space. With age, para-inflammatory changes have also been observed in the choroidal tissue, evidenced by 1) increased thickness of choroid; 2) increased number of CD45(+)CRIg(+) macrophages; 3) morphological abnormalities in choroidal melanocytes; and 4) fibrosis in choroidal tissue. An increased knowledge of contribution of retinal para-inflammation to various pathological conditions is essential for the better understanding of the pathogenesis of various age-related retinal diseases including diabetic retinopathy, glaucoma and age-related macular degeneration. 10.1016/j.preteyeres.2009.06.001
    The Unique Paired Retinal Vessels of the Gray Short-Tailed Opossum (Monodelphis domestica) and Their Relationship to Astrocytes and Microglial Cells. McMenamin Paul G,Golborne Cecilia Naranjo,Chen Xiangting,Wheaton Ben,Dando Samantha Anatomical record (Hoboken, N.J. : 2007) In marsupials that possess a retinal vasculature, the arterial and venous segments, down to the smallest calibre capillaries, have been shown to occur in pairs. This pattern is seen in the marsupial central nervous system (CNS) but not in other tissues in this group or in any tissues in eutherian mammals. The present study aimed to determine if the gray short-tailed opossum (Monodelphis domestica), a south American marsupial, possesses double retinal vessels. Secondly, we investigated the relationship between vessels and astrocytes and microglia, which are known to play pivotal roles in the blood retinal barrier and immune surveillance respectively. Eyes from M. domestica between 2 months and 33 months of age were examined by bright field and fluorescein angiography, resin histology, and wholemount immunostaining. Retinal vessels in this marsupial always occur in closely related pairs with the arteriolar limb usually on the vitread aspect. Branches penetrate the retina to form layers of paired capillaries as far as the outer nuclear layer. Dense networks of GFAP astrocytes enveloped the vitread aspect of vessels. No particularly strong association with blood vessels and ramified Iba1 and Ib4 microglia was noted. M. domestica possessed the unusual paired vasculature and capillary loops arrangement previously described in the marsupial CNS. These observations in a small laboratory-friendly marsupial open up new frontiers to investigate the factors that regulate paired blood vessel development and the functional significance of this arrangement when compared to the anastomotic pattern observed in the retina of eutherian mammals. Anat Rec, 300:1391-1400, 2017. © 2017 Wiley Periodicals, Inc. 10.1002/ar.23601