Publications by authors named "Thomas Langmann"

145 Publications

Inflammation in Viral Vector-Mediated Ocular Gene Therapy: A Review and Report From a Workshop Hosted by the Foundation Fighting Blindness, 9/2020.

Transl Vis Sci Technol 2021 Apr;10(4)

Foundation Fighting Blindness, Columbia, MD, USA.

Translational Relevance: Subclinical or clinical inflammation often arises during ocular gene therapy with viral vectors. Understanding the biological bases and impacts on efficacy are important for clinical management and the improvement of future therapies.
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http://dx.doi.org/10.1167/tvst.10.4.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024774PMC
April 2021

VEGFR1 signaling in retinal angiogenesis and microinflammation.

Prog Retin Eye Res 2021 Feb 25:100954. Epub 2021 Feb 25.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany. Electronic address:

Five vascular endothelial growth factor receptor (VEGFR) ligands (VEGF-A, -B, -C, -D, and placental growth factor [PlGF]) constitute the VEGF family. VEGF-A binds VEGF receptors 1 and 2 (VEGFR1/2), whereas VEGF-B and PlGF only bind VEGFR1. Although much research has been conducted on VEGFR2 to elucidate its key role in retinal diseases, recent efforts have shown the importance and involvement of VEGFR1 and its family of ligands in angiogenesis, vascular permeability, and microinflammatory cascades within the retina. Expression of VEGFR1 depends on the microenvironment, is differentially regulated under hypoxic and inflammatory conditions, and it has been detected in retinal and choroidal endothelial cells, pericytes, retinal and choroidal mononuclear phagocytes (including microglia), Müller cells, photoreceptor cells, and the retinal pigment epithelium. Whilst the VEGF-A decoy function of VEGFR1 is well established, consequences of its direct signaling are less clear. VEGFR1 activation can affect vascular permeability and induce macrophage and microglia production of proinflammatory and proangiogenic mediators. However the ability of the VEGFR1 ligands (VEGF-A, PlGF, and VEGF-B) to compete against each other for receptor binding and to heterodimerize complicates our understanding of the relative contribution of VEGFR1 signaling alone toward the pathologic processes seen in diabetic retinopathy, retinal vascular occlusions, retinopathy of prematurity, and age-related macular degeneration. Clinically, anti-VEGF drugs have proven transformational in these pathologies and their impact on modulation of VEGFR1 signaling is still an opportunity-rich field for further research.
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http://dx.doi.org/10.1016/j.preteyeres.2021.100954DOI Listing
February 2021

PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions.

Int J Mol Sci 2021 Jan 25;22(3). Epub 2021 Jan 25.

Department of Physiological Genomics, Biomedical Center, Ludwig-Maximilians-Universität München, D-82152 Planegg-Martinsried, Germany.

Müller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Müller glia has been reported earlier, their actual role for Müller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Müller cell-specific PDGF receptor alpha (PDGFRα) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFRα-deficient Müller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFRα ligand PDGF-BB prevented Müller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFRα KO Müller cells. Additionally, PDGFRα KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Müller glial PDGFRα is central for retinal functions under physiological conditions. In contrast, Müller cell-specific PDGFRα KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy-a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Müller cell homeostatic functions potentially interfering with a long-term positive outcome.
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http://dx.doi.org/10.3390/ijms22031174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865899PMC
January 2021

IFN-β signaling dampens microglia reactivity but does not prevent from light-induced retinal degeneration.

Biochem Biophys Rep 2020 Dec 26;24:100866. Epub 2020 Nov 26.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.

Chronic activation of microglia is associated with retinal degeneration, which makes them a potential therapeutic target for retinal degenerative diseases including age-related macular degeneration (AMD). Interferon-beta (IFN-β) is a potent immune regulator, commonly used for the treatment of multiple sclerosis patients. We have previously shown that IFN-β prevents microgliosis and choroidal neovascularization in a laser model of wet AMD. Here, we hypothesized that microglia modulation via IFN-β may also dampen mononuclear phagocyte reactivity and thereby protect from retinal degeneration in a light-damage paradigm mimicking some features of dry AMD. BALB/cJ mice received intraperitoneal injections of 10,000 U IFN-β or vehicle every other day; starting at the day of exposure to 15,000 lux white light for 1 h. Systemic treatment with IFN-β partially enhanced IFN-α/β receptor (IFNAR) signaling in the retina and reduced the number of reactivated microglia in the subretinal space. However, four days after light damage neither decreased expression of complement factors nor rescue of retinal thickness was found. We conclude that IFNAR signaling modulate retinal microglia but cannot prevent strong retinal degeneration as elicited by acute white light damage.
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http://dx.doi.org/10.1016/j.bbrep.2020.100866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704411PMC
December 2020

Microglia and Inflammatory Responses in Diabetic Retinopathy.

Front Immunol 2020 6;11:564077. Epub 2020 Nov 6.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Diabetic retinopathy is a vision-threatening disease affecting neurons and microvasculature of the retina. The development of this disease is associated with the action of inflammatory factors that are connected to the activation of microglial cells, the resident tissue macrophages of the CNS. In the quiescent state, microglial cells help maintain tissue homeostasis in the retina through phagocytosis and control of low-grade inflammation. However, prolonged tissue stress due to hyperglycemia primes microglia to become overly reactive with the concomitant production of pro-inflammatory cytokines and chemokines causing chronic inflammation. In this review, we provide evidence of microglial cell activation and pro-inflammatory molecules associated with the development and progression of diabetic retinopathy. We further highlight innovative animal models that can mimic the disease in humans and discuss strategies in modulating microglial-mediated inflammation as potential therapeutic approaches in managing the disease.
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http://dx.doi.org/10.3389/fimmu.2020.564077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681237PMC
May 2021

Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration.

J Neuroinflammation 2020 Nov 3;17(1):327. Epub 2020 Nov 3.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Joseph-Stelzmann-Str. 9, D-50931, Cologne, Germany.

Background: Retinal degenerative diseases significantly contribute to visual impairment and blindness. Microglia reactivity is a hallmark of neurodegenerative diseases including retinal cell death and immunomodulation emerges as a therapeutic option. Indole-3-carbinol (I3C) is a natural ligand of aryl hydrocarbon receptor (AhR), with potent immunomodulatory properties. Here, we hypothesized that I3C may inhibit microglia reactivity and exert neuroprotective effects in the light-damaged murine retina mimicking important immunological aspects of retinal degeneration.

Methods: BV-2 microglia were treated in vitro with I3C followed by lipopolysaccharide (LPS) stimulation to analyze pro-inflammatory and anti-oxidant responses by quantitative real-time PCR (qRT-PCR) and Western blots. Nitric oxide (NO) secretion, caspase 3/7 levels, phagocytosis rates, migration, and morphology were analyzed in control and AhR knockdown cells. I3C or vehicle was systemically applied to light-treated BALB/cJ mice as an experimental model of retinal degeneration. Pro-inflammatory and anti-oxidant responses in the retina were examined by qRT-PCR, ELISA, and Western blots. Immunohistochemical staining of retinal flat mounts and cryosections were performed. The retinal thickness and structure were evaluated by in vivo imaging using spectral domain-optical coherence tomography (SD-OCT).

Results: The in vitro data showed that I3C potently diminished LPS-induced pro-inflammatory gene expression of I-NOS, IL-1ß, NLRP3, IL-6, and CCL2 and induced anti-oxidants gene levels of NQO1, HMOX1, and CAT1 in BV-2 cells. I3C also reduced LPS-induced NO secretion, phagocytosis, and migration as important functional microglia parameters. siRNA-mediated knockdown of AhR partially prevented the previously observed gene regulatory events. The in vivo experiments revealed that I3C treatment diminished light-damage induced I-NOS, IL-1ß, NLRP3, IL-6, and CCL2 transcripts and also reduced CCL2, I-NOS, IL-1ß, p-NFkBp65 protein levels in mice. Moreover, I3C increased anti-oxidant NQO1 and HMOX1 protein levels in light-exposed retinas. Finally, I3C therapy prevented the accumulation of amoeboid microglia in the subretinal space and protected from retinal degeneration.

Conclusions: The AhR ligand I3C potently counter-acts microgliosis and light-induced retinal damage, highlighting a potential treatment concept for retinal degeneration.
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http://dx.doi.org/10.1186/s12974-020-01999-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640677PMC
November 2020

A mega-analysis of expression quantitative trait loci in retinal tissue.

PLoS Genet 2020 09 1;16(9):e1008934. Epub 2020 Sep 1.

Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

Significant association signals from genome-wide association studies (GWAS) point to genomic regions of interest. However, for most loci the causative genetic variant remains undefined. Determining expression quantitative trait loci (eQTL) in a disease relevant tissue is an excellent approach to zoom in on disease- or trait-associated association signals and hitherto on relevant disease mechanisms. To this end, we explored regulation of gene expression in healthy retina (n = 311) and generated the largest cis-eQTL data set available to date. Genotype- and RNA-Seq data underwent rigorous quality control protocols before FastQTL was applied to assess the influence of genetic markers on local (cis) gene expression. Our analysis identified 403,151 significant eQTL variants (eVariants) that regulate 3,007 genes (eGenes) (Q-Value < 0.05). A conditional analysis revealed 744 independent secondary eQTL signals for 598 of the 3,007 eGenes. Interestingly, 99,165 (24.71%) of all unique eVariants regulate the expression of more than one eGene. Filtering the dataset for eVariants regulating three or more eGenes revealed 96 potential regulatory clusters. Of these, 31 harbour 130 genes which are partially regulated by the same genetic signal. To correlate eQTL and association signals, GWAS data from twelve complex eye diseases or traits were included and resulted in identification of 80 eGenes with potential association. Remarkably, expression of 10 genes is regulated by eVariants associated with multiple eye diseases or traits. In conclusion, we generated a unique catalogue of gene expression regulation in healthy retinal tissue and applied this resource to identify potentially pleiotropic effects in highly prevalent human eye diseases. Our study provides an excellent basis to further explore mechanisms of various retinal disease etiologies.
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http://dx.doi.org/10.1371/journal.pgen.1008934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462281PMC
September 2020

The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye.

Nat Commun 2020 06 1;11(1):2709. Epub 2020 Jun 1.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, D-50931, Cologne, Germany.

Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1:TSPO mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.
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http://dx.doi.org/10.1038/s41467-020-16400-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264151PMC
June 2020

Translocator protein (18 kDa) (TSPO) ligands activate Nrf2 signaling and attenuate inflammatory responses and oxidative stress in human retinal pigment epithelial cells.

Biochem Biophys Res Commun 2020 07 29;528(2):261-268. Epub 2020 May 29.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931, Cologne, Germany. Electronic address:

Degeneration of the retinal pigment epithelium (RPE) is a hallmark of atrophic age-related macular degeneration (AMD). Microglia mediated inflammatory responses and oxidative stress are critical pathophysiological processes in the onset and progression of RPE degeneration. Given the central role of the RPE, strategies to protect these cells from damage caused by oxidative stress and inflammation present a promising therapeutic approach to mitigate AMD. Ligands for the translocator protein (18 kDa) (TSPO) have been shown to confer protection against retinal inflammatory responses and neurodegeneration by acting primarily through retinal glia. However, despite RPE cells demonstrating strong TSPO expression, it remains unclear whether TSPO ligands could also inhibit inflammatory responses of RPE cells. Here, we investigated the influence of three different TSPO ligands XBD173, PK11195 and Ro5-4864 on inflammatory responses in human ARPE-19 cells triggered by supernatants from reactive human microglial cells and the lysosomal destabilizer, LLOMe. Our findings revealed that TSPO ligands significantly inhibited proinflammatory gene expression, inflammasome-mediated caspase-1 activation, lipid accumulation and intracellular ROS levels in stressed ARPE-19 cells. Notably, TSPO ligands induced activation of Nrf2 pathway and its downstream regulated genes in ARPE-19 cells, with Hmox-1 being the most strongly upregulated gene. Collectively, our study indicates that TSPO ligands can enhance the Nrf2 antioxidant pathway in RPE cells and protect them from cellular damage resulting from inflammation and oxidative stress.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.114DOI Listing
July 2020

A Circulating MicroRNA Profile in a Laser-Induced Mouse Model of Choroidal Neovascularization.

Int J Mol Sci 2020 Apr 13;21(8). Epub 2020 Apr 13.

Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.

Choroidal neovascularization (CNV) is a pathological process in which aberrant blood vessels invade the subretinal space of the mammalian eye. It is a characteristic feature of the prevalent neovascular age-related macular degeneration (nAMD). Circulating microRNAs (cmiRNAs) are regarded as potentially valuable biomarkers for various age-related diseases, including nAMD. Here, we investigated cmiRNA expression in an established laser-induced CNV mouse model. Upon CNV induction in C57Bl/6 mice, blood-derived cmiRNAs were initially determined globally by RNA next generation sequencing, and the most strongly dysregulated cmiRNAs were independently replicated by quantitative reverse transcription PCR (RT-qPCR) in blood, retinal, and retinal pigment epithelium (RPE)/choroidal tissue. Our findings suggest that two miRNAs, mmu-mir-486a-5p and mmur-mir-92a-3p, are consistently dysregulated during CNV formation. Furthermore, in functional in vitro assays, a significant impact of mmu-mir-486a-5p and mmu-mir-92a-3p on murine microglial cell viability was observed, while mmu-mir-92a-3p also showed an impact on microglial mobility. Taken together, we report a robust dysregulation of two miRNAs in blood and RPE/choroid after laser-induced initiation of CNV lesions in mice, highlighting their potential role in pathology and eventual therapy of CNV-associated complications.
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http://dx.doi.org/10.3390/ijms21082689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216141PMC
April 2020

Major Predictive Factors for Progression of Early to Late Age-Related Macular Degeneration.

Ophthalmologica 2020 13;243(6):444-452. Epub 2020 Mar 13.

Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.

Introduction: We present a prediction model for progression from early/intermediate to advanced age-related macular degeneration (AMD) within 5.9 years.

Objectives: To evaluate the combined role of genetic, nongenetic, and phenotypic risk factors for conversion from early to late AMD over ≥5 years.

Methods: Baseline phenotypic characteristics were evaluated based on color fundus photography, spectral-domain optical coherence tomography, and infrared images. Genotyping for 36 single-nucleotide polymorphisms as well as systemic lipid and complement measurements were performed. Multivariable backward logistic regression resulted in a final prediction model.

Results And Conclusions: During a mean of 5.9 years of follow-up, 22.4% (n = 52) of the patients (n = 232) showed progression to late AMD. The multivariable prediction model included age, CFH variant rs1061170, pigment abnormalities, drusenoid pigment epithelial detachment (DPED), and hyperreflective foci (HRF). The model showed an area under the curve of 0.969 (95% confidence interval 0.948-0.990) and adequate calibration (Hosmer-Lemeshow test, p = 0.797). In addition to advanced age and carrying a CFH variant, pigment abnormalities, DPED, and HRF are relevant imaging biomarkers for conversion to late AMD. In clinical routine, an intensified monitoring of patients with a high-risk phenotypic profile may be suitable for the early detection of conversion to late AMD.
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http://dx.doi.org/10.1159/000507196DOI Listing
March 2020

Phenotype of Innate Immune Cells in Uveitis Associated with Axial Spondyloarthritis- and Juvenile Idiopathic Arthritis-associated Uveitis.

Ocul Immunol Inflamm 2020 Mar 11:1-10. Epub 2020 Mar 11.

Department of Ophthalmology, Ophtha-Lab at St. Franziskus Hospital, Münster, Germany.

: To analyze circulating immune cells in patients with anterior uveitis (AU) associated to axial spondyloarthritis (SpA), or juvenile idiopathic arthritis (JIA).: Venous blood samples were collected from healthy controls (n = 16), and either SpA (n = 19) or JIA (n = 23) patients with associated anterior uveitis (AU) during active flare, or after ≥3 months of inactivity. Frequencies of CD56, MHC-I, and S100A9 monocytes, CCR7 dendritic cells, CD56 natural killer (NK) cells and CD3CD56 T-cells were analyzed via flow cytometry. Serum S100A8/A9 levels were determined via ELISA.: SpA patients showed a reduced frequency of CD56 NK cells during uveitis activity, a constitutively activated monocyte phenotype, and elevated S100A8/A9 serum levels. In contrast, JIAU patients showed elevated frequencies of CD56 monocytes and CCR7 DC.: Phenotype of peripheral immune cells differ between patients, probably contributing to different courses of acute onset AU in SpA and insidious onset AU in JIAU patients.: AU: anterior uveitis, AR: arthritis, JIA: juvenile idiopathic arthritis, SpA: axial spondyloarthritis.
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http://dx.doi.org/10.1080/09273948.2020.1715449DOI Listing
March 2020

Phenotypic Differences in Primary Murine Microglia Treated with NOD1, NOD2, and NOD1/2 Agonists.

J Mol Neurosci 2020 Apr 7;70(4):600-609. Epub 2020 Jan 7.

Ophtha-Lab, Ophthalmic Center at St.Franziskus Hospital, Münster, Germany.

The purpose of the study was studying the influence of different NOD agonists on the morphological phenotype of primary murine microglia and to examine their influence on characteristic cytokines. Primary CD11b-positive cells were isolated from the brain of neonatal mice. The microglial phenotype of the cells was examined by ionized calcium-binding adapter molecule (Iba)1 staining. After14 days in culture, these cells were stimulated by iE-DAP, L18-MDP, or M-TriDAP as NOD1, NOD2, and NOD1/2 agonists, respectively. The cellular morphology was recorded and compared to the phenotype of cells cultured in medium alone or after LPS stimulation. The cells developed a specific phenotype only after treatment with the NOD2 agonist L18-MDP. These cells were characterized by straight extensions carrying tiny spikes and had a high ramification index. This was in sharp contrast to all other treatments, which always resulted in an amoeboid phenotype typically shown by activated microglia in vivo and by cultured microglia in vitro. The staining intensity of IL-6 and TNF-α did not reveal any clear difference independent of the NOD agonist treatment. In contrast, an increased staining intensity was observed for IL-10 after L18-MDP treatment. The NOD2 agonist L18-MDP induced a morphologically distinct phenotype characterized by microspike-decorated dendritiform extensions and a high degree of ramification in primary murine microglia. Increased ramification index and elevated staining intensity of anti-inflammatory IL-10 as hallmarks suggest that a M2-like phenotype of microglia was induced.
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http://dx.doi.org/10.1007/s12031-019-01466-xDOI Listing
April 2020

The role of lymphocytes and phagocytes in age-related macular degeneration (AMD).

Cell Mol Life Sci 2020 Mar 2;77(5):781-788. Epub 2020 Jan 2.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931, Cologne, Germany.

Age-related macular degeneration (AMD) is a leading cause of visual impairment of the elderly population. Since AMD is a multifactorial age-related disease with various genetic risk factors, the understanding of its complex pathophysiology is still limited. However, animal experiments, genome-wide association data and the molecular profiling of AMD patient samples have highlighted a key role of systemic and local immune processes that contribute to this chronic eye disease. In this overview article, we concentrate on the role of lymphocytes and mononuclear phagocytes and their interplay in triggering a persistent immune response in the AMD retina. We preferentially review findings from human immune cell analyses and complement these with related findings in experimental models. We conclude that both immune cell types as their signaling network may be a rich source to identify novel molecular targets for immunomodulation in AMD.
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http://dx.doi.org/10.1007/s00018-019-03419-4DOI Listing
March 2020

ERG Alteration Due to the rd8 Mutation of the Crb1 Gene in Cln3 Mice.

Adv Exp Med Biol 2019 ;1185:395-400

Department of Ophthalmology, University Eye Clinic Regensburg, Regensburg, Germany.

Mattapallil et al. described that vendor lines for C57BL/6 N mice may carry the rd8 mutation that leads to an ocular phenotype, which could be mistaken for an induced retinal degeneration. This mouse strain is widely used in ophthalmic research as a background for modeling retinal degeneration. In the process of studying Cln3 knock-in mice on a C57BL/6 N background, we became aware of this issue. The aim of this study thus was to use electroretinography to investigate the age-dependent functional loss in Cln3 mice and compare it to C57BL/6 J mice.The scotopic and photopic amplitudes of the a-wave and b-wave decrease significantly in mutant mice with increasing age, and the implicit time is prolonged. Especially the oscillatory potentials arising from inner retinal interaction seem to be notably affected by the rd8 mutation. Surprisingly, the amplitudes in young C57BL/6 J mice were lower than those measured in C57BL/6 N at any time point.Our results indicate that the rd8 mutation present in C57BL/6 N mice affects the function of the inner and outer retina. This is surprising given that the major retinal morphological alterations due to the rd8 mutation are found in the outer retina.We conclude that the rd8 mutation does affect the retinal function in Cln3 mice in a variable manner. Epigenetic factors and modifying genes lead to a phenotype shift in these mice. Interpreting the results of previous studies in mutant mice on C57BL/6 N background is challenging as comparing results obtained in independent studies or on other mouse backgrounds may be misleading. Using littermates as controls remains the only valid option.
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http://dx.doi.org/10.1007/978-3-030-27378-1_65DOI Listing
February 2020

AMD-Associated HTRA1 Variants Do Not Influence TGF-β Signaling in Microglia.

Adv Exp Med Biol 2019 ;1185:3-7

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Genetic variants of high-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are associated with age-related macular degeneration (AMD). One HTRA1 single nucleotide polymorphism (SNP) is situated in the promotor region (rs11200638) resulting in increased expression, while two synonymous SNPs are located in exon 1 (rs1049331:C > T, rs2293870:G > T). HtrA1 is known to inhibit transforming growth factor-β (TGF-β) signaling, a pathway regulating quiescence of microglia, the resident immune cells of the brain and retina. Microglia-mediated immune responses contribute to AMD pathogenesis. It is currently unclear whether AMD-associated HTRA1 variants influence TGF-β signaling and microglia phenotypes. Here, we show that an HtrA1 isoform carrying AMD-associated SNPs in exon 1 exhibits increased proteolytic activity. However, when incubating TGF-β-treated reactive microglia with HtrA1 protein variants, neither the wildtype nor the SNP-associated isoforms changed microglia activation in vitro.
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http://dx.doi.org/10.1007/978-3-030-27378-1_1DOI Listing
February 2020

Loss of IL-10 Promotes Differentiation of Microglia to a M1 Phenotype.

Front Cell Neurosci 2019 9;13:430. Epub 2019 Oct 9.

Department of Ophthalmology and Ophtha-Lab at St. Franziskus-Hospital, Münster, Germany.

Microglia represent the primary resident immune cells of the central nervous system (CNS) and modulate local immune responses. Depending on their physiological functions, microglia can be classified into pro- (M1) and anti-inflammatory (M2) phenotype. Interleukin (IL)-10 is an important modulator of neuronal homeostasis, with anti-inflammatory and neuroprotective functions, and can be released by microglia. Here, we investigated how IL-10 deficiency affected the M1/2 polarization of primary microglia upon lipopolysaccharide (LPS) stimulation . Microglia phenotypes were analyzed via flow cytometry. Cytokine and chemokine secretion were examined by ELISA and bead-based multiplex LEGENDplex. Our results showed that genetic depletion of IL-10 led to elevated M1 like phenotype (CD86+ CD206-) under pro-inflammatory conditions associated with increased frequency of IL-6+, TNF-α+ cells and enhanced release of several pro-inflammatory chemokines. Absence of IL-10 led to an attenuated M2 like phenotype (CD86- CD206+) and a reduced secretion of TGF-β1 upon LPS stimulation. In conclusion, IL-10 deficiency may promote the polarization of microglia into M1-prone phenotype under pro-inflammatory conditions.
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http://dx.doi.org/10.3389/fncel.2019.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794388PMC
October 2019

Systemic knockout of Tspo in mice does not affect retinal morphology, function and susceptibility to degeneration.

Exp Eye Res 2019 11 25;188:107816. Epub 2019 Sep 25.

Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, Switzerland; Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland; Neuroscience Center, University of Zurich, Zurich, Switzerland. Electronic address:

Translocator protein (18 kDa) (TSPO) is a mitochondrial protein expressed by reactive microglia and astrocytes at the site of neuronal injury. Although TSPO function has not been fully determined, synthetic TSPO ligands have beneficial effects on different pathologies of the central nervous system, including the retina. Here, we studied the pattern of Tspo expression in the aging human retina and in two mouse models of retinal degeneration. Using a newly generated Tspo-KO mouse, we investigated the impact of the lack of TSPO on retinal morphology, function and susceptibility to degeneration. We show that TSPO was expressed in both human and mouse retina and retinal pigment epithelium (RPE). Tspo was induced in the mouse retina upon degeneration, but constitutively expressed in the RPE. Similarly, TSPO expression levels in healthy human retina and RPE were not differentially regulated during aging. Tspo-KO mice had normal retinal morphology and function up to 48 weeks of age. Photoreceptor loss caused either by exposure to excessive light levels or by a mutation in the phosphodiesterase 6b gene was not affected by the absence of Tspo. The reactivity states of retinal mononuclear phagocytes following light-damage were comparable in Tspo-KO and control mice. Our data suggest that lack of endogenous TSPO does not directly influence the magnitude of photoreceptor degeneration or microglia activation in these two models of retinal degeneration. We therefore hypothesize that the interaction of TSPO with its ligands may be required to modulate disease progression.
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http://dx.doi.org/10.1016/j.exer.2019.107816DOI Listing
November 2019

Microglia in Retinal Degeneration.

Front Immunol 2019 20;10:1975. Epub 2019 Aug 20.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.
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http://dx.doi.org/10.3389/fimmu.2019.01975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710350PMC
October 2020

Anti-VEGF-A/ANG2 combotherapy limits pathological angiogenesis in the eye: a replication study.

EMBO Mol Med 2019 05;11(5)

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

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http://dx.doi.org/10.15252/emmm.201910362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505573PMC
May 2019

Co-inhibition of PGF and VEGF blocks their expression in mononuclear phagocytes and limits neovascularization and leakage in the murine retina.

J Neuroinflammation 2019 Feb 7;16(1):26. Epub 2019 Feb 7.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931, Cologne, Germany.

Background: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes.

Methods: CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA.

Results: Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups.

Conclusions: Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.
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http://dx.doi.org/10.1186/s12974-019-1419-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366121PMC
February 2019

Transcriptional regulation of Translocator protein (18 kDa) (TSPO) in microglia requires Pu.1, Ap1 and Sp factors.

Biochim Biophys Acta Gene Regul Mech 2018 12 6;1861(12):1119-1133. Epub 2018 Nov 6.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, D-50931 Cologne, Germany; Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. Electronic address:

Mitochondrial Translocator protein (18 kDa) (TSPO) is strongly expressed in reactive microglia and serves as a therapeutic target for alleviation of neuronal degeneration. However, little is known about TSPO's transcriptional regulation in microglia. The aim of this study was to identify genetic elements and transcription factors required for basal and inducible TSPO expression in microglia. Murine Tspo promoter was cloned into the pGL4.10 luciferase vector and functionally characterized in BV-2 cells. Deletion mutagenesis indicated that -845 bases upstream were sufficient to reconstitute near maximal promoter activity in BV-2. Deletion of -593 to -520 sequences, which harbour an Ap1, Ets.2 and Nkx3.1 site which also serves as a non-canonical binding site for Sp1-family transcription factors, led to a dramatic decrease in both basal and LPS induced promoter activity. Further deletion of -168 to -39 sequences, which contains four GC boxes, also led to a significant decrease in promoter activity. Targeted mutations of Ap1, Ets.2, Nkx3.1/Sp1/3/4 and the GC boxes led to significant decreases in promoter activity. ChIP-qPCR revealed that Pu.1, Ap1, Stat3, Sp1, Sp3 and Sp4 bind to the endogenous Tspo promoter. Notably, binding of these factors, with the exception of Stat3, was significantly enhanced upon LPS treatment. RNAi silencing of Pu.1, cJun, cFos, Sp1, Sp3, Sp4 and Stat3 strongly lowered Tspo promoter activity while Ap1 silencing inhibited LPS induced increase in Tspo protein levels. These findings demonstrate that consensus binding sequences for Ap1, Ets.2, distal as well as proximal Sp1/3/4 sites regulate basal and LPS induced Tspo promoter activity in microglia.
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http://dx.doi.org/10.1016/j.bbagrm.2018.10.018DOI Listing
December 2018

Testing for Known Retinal Degeneration Mutants in Mouse Strains.

Methods Mol Biol 2019 ;1834:45-58

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.

Approximately 93 years ago at the zoological laboratories of Harvard University, Keeler, a medical geneticist, discovered a retina from a male albino mouse that was completely devoid of visual cells (rods). This rodless mouse was to be the first ever reported murine model of retinal degeneration. Over the years, naturally occurring retinal degeneration mouse mutants have been identified in several common laboratory inbred lines including FVB/NJ (Pde6b) and C57BL/6N (Crb1). It is therefore imperative that vision researchers employing other genetically induced retinal degeneration models and experimental models such as laser-induced choroidal neovascularization (CNV) or bright white-light exposure screen for such naturally occurring mutations to prevent costly misinterpretations. In this regard, we describe herein simple molecular-based techniques for screening the presence of some commonly encountered rd mutations (Pde6b, Crb1, Pde6b, and Rpe65).
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http://dx.doi.org/10.1007/978-1-4939-8669-9_3DOI Listing
April 2019

Correction: Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.

Genet Med 2019 Aug;21(8):1998

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

The original version of this Article contained an error in the spelling of the author Anja K. Mayer, which was incorrectly given as Anja Kathrin Mayer. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0305-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609298PMC
August 2019

Modulation of three key innate immune pathways for the most common retinal degenerative diseases.

EMBO Mol Med 2018 10;10(10)

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany

This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age-related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.
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http://dx.doi.org/10.15252/emmm.201708259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180304PMC
October 2018

Neuroprotective Effects of FGF2 and Minocycline in Two Animal Models of Inherited Retinal Degeneration.

Invest Ophthalmol Vis Sci 2018 09;59(11):4392-4403

Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia and Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.

Purpose: The purpose of this study was to study the effect of minocycline and several neurotrophic factors, alone or in combination, on photoreceptor survival and macro/microglial reactivity in two rat models of retinal degeneration.

Methods: P23H-1 (rhodopsin mutation), Royal College of Surgeon (RCS, pigment epithelium malfunction), and age-matched control rats (Sprague-Dawley and Pievald Viro Glaxo, respectively) were divided into three groups that received at P10 for P23H-1 rats or P33 for RCS rats: (1) one intravitreal injection (IVI) of one of the following neurotrophic factors: ciliary neurotrophic factor (CNTF), pigment epithelium-derived factor (PEDF), or basic fibroblast growth factor (FGF2); (2) daily intraperitoneal administration of minocycline; or (3) a combination of IVI of FGF2 and intraperitoneal minocycline. All animals were processed 12 days after treatment initiation. Retinal microglial cells and cone photoreceptors were immunodetected and analyzed qualitatively in cross sections. The numbers of microglial cells in the different retinal layers and number of nuclei rows in the outer nuclear layer (ONL) were quantified.

Results: IVI of CNTF, PEDF, or FGF2 improved the morphology of the photoreceptors outer segment, but only FGF2 rescued a significant number of photoreceptors. None of the trophic factors had qualitative or quantitative effects on microglial cells. Minocycline treatment reduced activation and migration of microglia and produced a significant rescue of photoreceptors. Combined treatment with minocycline and FGF2 had higher neuroprotective effects than each of the treatments alone.

Conclusions: In two animal models of photoreceptor degeneration with different etiologies, minocycline reduces microglial activation and migration, and FGF2 and minocycline increase photoreceptor survival. The combination of FGF2 and minocycline show greater neuroprotective effects than their isolated effects.
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http://dx.doi.org/10.1167/iovs.18-24621DOI Listing
September 2018

The Phenotype of Monocytes in Anterior Uveitis Depends on the HLA-B27 Status.

Front Immunol 2018 30;9:1773. Epub 2018 Jul 30.

Department of Ophthalmology and Ophtha-Laboratory at St. Franziskus Hospital, Münster, Germany.

HLA-B27 is the allele most frequently associated with human anterior uveitis. The majority of HLA-B27-positive [acute anterior uveitis (AAU)] patients develop clinically distinct symptoms with acute symptomatic onset of flare and a recurrent disease course characterized by a massive cellular ocular infiltrate during uveitis relapse. By contrast, uveitis in HLA-B27-negative [idiopathic anterior uveitis (IAU)] patients tends to develop a clinically less fulminant, more chronic, and typically asymptomatic disease course. To analyze systemic immune responses in the different uveitis entities, we analyzed peripheral blood cells by flow cytometry. In addition, as a pro-inflammatory biomarker serum, S100A8/A9 levels were quantified by ELISA from patients with AAU ( = 27) and IAU ( = 21), and in healthy controls ( = 30). Data were obtained either during active uveitis flare or after 3 months of inactivity. IAU patients showed a transiently increased frequency of CD56- and CD163-positive monocytes and of both granulocytic myeloid-derived suppressor cells and Th17 cells during active uveitis. By contrast, AAU patients showed an elevated frequency of monocytes, activated T cells, and elevated S100A8/A9 serum levels during clinically quiescent disease. The differentially regulated response of both innate and adaptive immune cells in the blood may be related to the clinically distinct characteristics of the two different uveitis entities.
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http://dx.doi.org/10.3389/fimmu.2018.01773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077321PMC
September 2019

Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage.

Dis Model Mech 2018 09 5;11(9). Epub 2018 Sep 5.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, 50931 Cologne, Germany

Juvenile neuronal ceroid lipofuscinosis (jNCL) is a rare but fatal inherited lysosomal storage disorder mainly affecting children. The disease is caused by mutations in the gene that lead to the accumulation of storage material in many tissues, prominent immune responses and neuronal degeneration. One of the first symptoms is vision loss followed by motor dysfunction and mental decline. The established mouse model mimics many pathological features of the human disease except the retinal phenotype, which is very mild and occurs only very late in these mice. Here, we first carefully analyzed the retinal structure and microglia responses in these animals. While prominent autofluorescent spots were present in the fundus, only a moderate reduction of retinal thickness and no prominent microgliosis was seen in young CLN3-deficient mice. We next genetically introduced a light-sensitive RPE65 variant and established a light-damage paradigm that showed a high susceptibility of young mice after exposure to 10,000 lux bright light for 30 min. Under these 'low light' conditions, CLN3-deficient mice showed a strong retinal degeneration, microglial activation, deposition of autofluorescent material and transcriptomic changes compared to wild-type animals. Finally, we treated the light-exposed animals with the immunomodulatory compound minocycline, and thereby rescued the retinal phenotype and diminished microgliosis. Our findings indicate that exposure to specific light conditions accelerates CLN3-dependent retinal degeneration, and that immunomodulation by minocycline could be a possible treatment option to delay vision loss in jNCL patients.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.033597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176999PMC
September 2018

Microglia Activation and Immunomodulatory Therapies for Retinal Degenerations.

Front Cell Neurosci 2018 21;12:176. Epub 2018 Jun 21.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.

A chronic pro-inflammatory environment is a hallmark of retinal degenerative diseases and neurological disorders that affect vision. Inflammatory responses during retinal pathophysiology are orchestrated by microglial cells which constitute the resident immune cell population. Following activation, microglia cells lose their ramified protrusions, proliferate and rapidly migrate to the damaged areas and resolve tissue damage. However, sustained presence of tissue stress primes microglia to become overreactive and results in the excessive production of pro-inflammatory mediators that favor retinal degenerative changes. Consequently, interventions aimed at overriding microglial pro-inflammatory and pro-oxidative properties may attenuate photoreceptor demise and preserve retinal integrity. We highlight the positive effects of ligands for the translocator protein 18 kDa (TSPO) and the cytokine interferon beta (IFN-β) in modulating microgliosis during retinal pathologies and discuss their plausible mechanisms of action.
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http://dx.doi.org/10.3389/fncel.2018.00176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021747PMC
June 2018

Resveratrol induces dynamic changes to the microglia transcriptome, inhibiting inflammatory pathways and protecting against microglia-mediated photoreceptor apoptosis.

Biochem Biophys Res Commun 2018 06 4;501(1):239-245. Epub 2018 May 4.

Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, D-50931, Cologne, Germany. Electronic address:

Microglia activation is central to the pathophysiology of retinal degenerative disorders. Resveratrol, a naturally occurring non-flavonoid phenolic compound present in red wine has potent anti-inflammatory and immunomodulatory properties. However, molecular mechanisms by which resveratrol influences microglial inflammatory pathways and housekeeping functions remain unclear. Here, we first studied the immuno-modulatory effects of resveratrol on BV-2 microglial cells at the transcriptome level using DNA-microarrays and selected qRT-PCR analyses. We then analyzed resveratrol effects on microglia morphology, phagocytosis and migration and estimated their neurotoxicity on 661 W photoreceptors by quantification of caspase 3/7 levels. We found that resveratrol effectively blocked gene expression of a broad spectrum of lipopolysaccharide (LPS)-induced pro-inflammatory molecules, including cytokines and complement proteins. These transcriptomic changes were accompanied by potent inhibition of LPS-induced nitric oxide secretion and reduced microglia-mediated apoptosis of 661 W photoreceptor cultures. Our findings highlight novel targets involved in the anti-inflammatory and neuroprotective action of resveratrol against neuroinflammatory responses.
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http://dx.doi.org/10.1016/j.bbrc.2018.04.223DOI Listing
June 2018