Table 3 - uploaded by Peter Wiedemann
Content may be subject to copyright.
Source publication
Macrophages have long been known to play a major role in the pathogenesis of proliferative vitreoretinal disorders. Using the monoclonal antibodies EBM11 (pan macrophage), 27E10 (early inflammatory stage marker), and RM3/1 (healing phase marker), different subpopulations of macrophages were differentiated in surgically removed membranes from patien...
Similar publications
Purpose
Advanced glycation endproducts (AGEs) and their precursors α-dicarbonyls are implicated in the progression of diabetic retinopathy. The purpose of this study was to assess AGEs and α-dicarbonyls in the vitreous of patients with type 2 diabetes mellitus (T2DM) with early stages or absence of diabetic retinopathy.
Methods
We examined vitreou...
Citations
... A pivotal characteristic of PVR is the formation of myofibroblast membranes from transdifferentiated RPE cells and other cell types, including macrophages (132). Macrophages are considered one of the most crucial inflammatory cell types (133). By comparing vitreous samples from patients with PVR and uncomplicated retinal detachment, researchers have noted a significant increase in the number of monocytes/macrophages in vitreous samples from patients with PVR. ...
... Throughout this process, the levels of growth factors, such as IFN-γ, VEGF, platelet-derived growth factor BB, placental growth factor and angiopoietin-2, surge, potentially fostering the survival, proliferation and EMT of RPE cells. The formation of contractile membranes and the secretion of growth factors are closely linked to M2 macrophages (133,138). Studies based on vitreous samples from human patients have indicated that M2 macrophage-derived microparticles can stimulate the proliferation and migration of RPE cells by activating the PI3K/AKT/mTOR signalling pathway (139), thereby contributing to the pathogenesis of vitreoretinal diseases. ...
Macrophages form a crucial component of the innate immune system, and their activation is indispensable for various aspects of immune and inflammatory processes, tissue repair, and maintenance of the balance of the body's state. Macrophages are found in all ocular tissues, spanning from the front surface, including the cornea, to the posterior pole, represented by the choroid/sclera. The neural retina is also populated by specialised resident macrophages called microglia. The plasticity of microglia/macrophages allows them to adopt different activation states in response to changes in the tissue microenvironment. When exposed to various factors, microglia/macrophages polarise into distinct phenotypes, each exhibiting unique characteristics and roles. Furthermore, extensive research has indicated a close association between microglia/macrophage polarisation and the development and reversal of various intraocular diseases. The present article provides a review of the recent findings on the association between microglia/macrophage polarisation and ocular pathological processes (including autoimmune uveitis, optic neuritis, sympathetic ophthalmia, retinitis pigmentosa, glaucoma, proliferative vitreoretinopathy, subretinal fibrosis, uveal melanoma, ischaemic optic neuropathy, retinopathy of prematurity and choroidal neovascularization). The paradoxical role of microglia/macrophage polarisation in retinopathy of prematurity is also discussed. Several studies have shown that microglia/macrophages are involved in the pathology of ocular diseases. However, it is required to further explore the relevant mechanisms and regulatory processes. The relationship between the functional diversity displayed by microglia/macrophage polarisation and intraocular diseases may provide a new direction for the treatment of intraocular diseases.
... In advanced stages of DR, such as PDR and diabetic macular edema, immune cells and mediators play important roles in disease progression [19,20,[23][24][25]. Indeed, macrophages have been shown to play a pivotal role in PDR and diabetic macular edema development, by invading the retina [24,26,27]. High levels of VEGF, a potent proangiogenic factor, are expressed in the retinas of diabetic patients, resulting in marked increases in intraocular VEGF concentration correlating with the presence of soft exudates, intraretinal microvascular abnormality, venous bleeding, venous loops, and neovascularization [19,28]. ...
Various immune mediators identified to date are associated with the development of advanced forms of diabetic retinopathy (DR), such as proliferative DR and diabetic macular edema, although the exact pathophysiological mechanisms of early stages of DR such as simple DR remain unclear. We determined the immune mediator profile in the aqueous humor of eyes with simple DR. Fifteen eyes of fifteen patients with simple DR were studied. Twenty-two eyes of twenty-two patients with cataracts and no DR served as controls. Undiluted aqueous humor samples were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 32 immune mediators comprising 13 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monokine induced by interferon-γ, basic fibroblast growth factor (bFGF), Fas ligand, granzyme A, granzyme B, interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), angiogenin, tumor necrosis factor-α, and CD40 ligand. Among the 32 immune mediators, 10 immune mediators, including bFGF, CD40 ligand, fractalkine, G-CSF, IL-6, IL-8, MIP-α, MIP-1β, and VEGF, showed significantly higher aqueous humor concentrations and the Fas ligand had significantly lower concentration (p < 0.05) in eyes with simple DR compared with control eyes. Of these 10 cytokines with significant concentration alteration, protein–protein interaction analysis revealed that 8 established an intricate interaction network. Various immune mediators may contribute to the pathogenesis of simple DR. Attention should be given to the concentrations of immune mediators in ocular fluids even in simple DR. Large-scale studies are warranted to assess whether altered aqueous humor concentrations of these 10 immune mediators are associated with an increased risk of progression to advanced stages of DR.
... Several pieces of laboratory evidence have revealed their essential role in the pathological changes that lead to PVR. Inflammatory cells release cytokines and mitogen factors that stimulate RPE and glial cells to transdifferentiate, proliferate, and deposit fibrous tissue, resulting in epiretinal and subretinal membrane formation [27][28][29][30][31]. while the pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, is secreted apically [21,22]. During embryogenesis, the cells' ability to switch between the epithelial and the mesenchymal statuses is crucial for the development of the human body [21]. ...
... Several pieces of laboratory evidence have revealed their essential role in the pathological changes that lead to PVR. Inflammatory cells release cytokines and mitogen factors that stimulate RPE and glial cells to transdifferentiate, proliferate, and deposit fibrous tissue, resulting in epiretinal and subretinal membrane formation [27][28][29][30][31]. The most important factors involved in this process are the platelet-derived growth factor (PDGF), the hepatocyte growth factor (HGF), the VEGF, the Epidermal Growth Factor (EGF), the granulocyte colony stimulating factor (G-CSF), the fibroblast growth factors a and b (aFGF and bFGF), the insulin-like growth factor 1 (IGF1), the transforming growth factors α and β (TGF-α and TGF-β), the tumor necrosis factor α (TNF-α), the interferons β and γ (IFN-β and INFγ), the interleukins 1, 1β, 6, 8, and 11(IL-1, IL-1β, IL-6, IL-8 ,and The most important factors involved in this process are the platelet-derived growth factor (PDGF), the hepatocyte growth factor (HGF), the VEGF, the Epidermal Growth Factor (EGF), the granulocyte colony stimulating factor (G-CSF), the fibroblast growth factors a and b (aFGF and bFGF), the insulin-like growth factor 1 (IGF1), the transforming growth factors α and β (TGF-α and TGF-β), the tumor necrosis factor α (TNF-α), the interferons β and γ (IFN-β and INFγ), the interleukins 1, 1β, 6, 8, and 11(IL-1, IL-1β, IL-6, IL-8, and IL-11), and chemokines, such as the ligand of the chemokines CC 3, 4, and 5 (CCL3, CCL4, and CCL5) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46]. ...
Proliferative vitreoretinopathy (PVR) remains the main cause of failure after retinal detachment (RD) surgery. Despite the development of modern technologies and sophisticated techniques for the management of RD, the growth of fibrocellular membranes within the vitreous cavity and on both sides of the retinal surface, as well as intraretinal fibrosis, can compromise surgical outcomes. Since 1983, when the term PVR was coined by the Retina Society, a lot of knowledge has been obtained about the physiopathology and risk factors of PVR, but, despite the proposal of a lot of therapeutic challenges, surgical skills seem to be the only effective way to manage PVR complications.
... In addition to inflammation-related factors, inflammatory cells, such as activated microglia, also contribute to the pathogenesis of DME and DR [62]. In diabetic eyes, hyperglycemia-induced activation of retinal microglia and infiltration of immune cells, including macrophages, lymphocytes, and neutrophils, have been reported [63][64][65]. ...
Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.
... Previous studies have identified macrophages as an important risk factor for PVR development. 19,28 In addition, macrophage-derived MPs, especially those derived from M2-phenotype macrophages, showed pathogenic effects in, for example, tumor invasion and fibrogenesis. [29][30][31] To determine whether the increased macrophage-derived MPs in vitreous samples were of the M1 or M2 phenotype, we performed triple-labeling with the CD68 antibody PerCP (pan-macrophage marker), CD80 antibody PE (M1 macrophage marker), and FITC-CD163 (M2 macrophage marker) of macrophage-derived MPs isolated from control, patients with RRD with PVR, and patients with traumatic Values are mean ± SD. * P < 0.5; ** P < 0.1; *** P < 0.001 versus control group by one-way ANOVA. ...
Purpose:
To characterize vitreous microparticles (MPs) in patients with traumatic proliferative vitreoretinopathy (PVR) and investigate their role in PVR pathogenesis.
Methods:
Vitreous MPs were characterized in patients with traumatic PVR, patients with rhegmatogenous retinal detachment (RRD) complicated with PVR, and control subjects by flow cytometry. The presence of M2 macrophages in epiretinal membranes was measured by immunostaining. Vitreous cytokines were quantified by ELISA assay. For in vitro studies, MPs isolated from THP-1 cell differentiated M1 and M2 macrophages, termed M1-MPs and M2-MPs, were used. The effects and mechanisms of M1-MPs and M2-MPs on RPE cell proliferation, migration, and epithelial to mesenchymal transition were analyzed.
Results:
Vitreous MPs derived from photoreceptors, microglia, and macrophages were significantly increased in patients with traumatic PVR in comparison with control and patients with RRD (PVR), whereas no significance was identified between the two control groups. M2 macrophages were present in epiretinal membranes, and their signature cytokines were markedly elevated in the vitreous of patients with traumatic PVR. Moreover, MPs from M2 macrophages were increased in the vitreous of patients with traumatic PVR. In vitro analyses showed that M2-MPs promoted the proliferation and migration of RPE cells via activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. However, M2-MPs did not induce the expression of fibrotic proteins, including fibronectin, α-smooth muscle actin, and N-cadherin in RPE cells.
Conclusions:
This study demonstrated increased MP shedding in the vitreous of patients with traumatic PVR; specifically, MPs derived from M2 polarized macrophages may contribute to PVR progression by stimulating RPE cell proliferation and migration.
... This ultimately leads to the formation of epiretinal and subretinal membranes that may cause retinal redetachment upon contraction. Several studies have thus found macrophages present in the vitreous and inside the retinal tissue in human PVR samples [19][20][21][22]. Moreover, it has been demonstrated that the presence of these cells is associated with a high risk of developing PVR [19,23]. ...
... These findings are concordant with those of Ricker et al. which reported that both CXCL10 and CCL11 levels were higher in patients who developed postoperative PVR [10]. In addition, several immunohistochemical studies have demonstrated the presence of macrophages and lymphocytes in PVR membranes, further confirming the crucial role of inflammation in the PVR process [19][20][21][22]41]. ...
Purpose
To compare the expression profiles of various cytokines and chemokines in vitreous samples from patients with retinal detachment (RD) to those from controls and to analyze their association with various clinical features.
Methods
In this prospective study, undiluted vitreous fluid was obtained from 41 patients with primary RD and 33 controls with macular hole or vitreomacular traction. A multiplex bead immunoassay was performed to determine the expression of 27 inflammatory mediators.
Results
Eleven mediators were significantly upregulated in the vitreous of RD patients compared with controls, including the following: cytokines IL-1ra, IL-6, IL-7, IL-8, IFN-γ; chemokines CCL2, CCL3, CCL4, CXCL10 and CCL11 and growth factor G-CSF. Correlation analyses showed that levels of IL-1ra, CXCL10, CCL11 and G-CSF were positively correlated to the extent of detachment, while those of IL-1ra and CXCL10 were associated with the duration of detachment. There was also a positive association between the concentrations of CXCL10 and CCL11 and preoperative flare values. Additional analysis revealed that flare values and both CXCL10 and CCL11 levels were significantly higher in eyes with grade B or C proliferative vitreoretinopathy (PVR).
Conclusion
Our results confirm that RD induces a marked inflammatory response with a complex cytokine network. We identified proteins specifically linked to several clinical features that might contribute to photoreceptor degeneration and PVR-related redetachment. These proteins may represent potential therapeutic targets for improving the anatomical and functional outcomes of RD surgery.
... Platelet aggregation is maintained in rats for up to 9 months of hyperglycemia (275), and in humans with diabetes, platelet-fibrin thrombi have been observed in retinal capillaries (55). In addition, retinal tissue macrophages were found in hyperglycemic rats after 2 and 9 months of hyperglycemia (519), and in the retinas of diabetic individuals with PDR (163). However, to our knowledge, the cause and effect relationship of platelets and macrophages to the development of diabetic retinopathy has not been established. ...
In this article, we present a discussion of diabetes and its complications, including the macrovascular and microvascular effects, with the latter of consequence to the retina. We will discuss the anatomy and physiology of the retina, including aspects of metabolism and mechanisms of oxygenation, with the latter accomplished via a combination of the retinal and choroidal blood circulations. Both of these vasculatures are altered in diabetes, with the retinal circulation intimately involved in the pathology of diabetic retinopathy. The later stages of diabetic retinopathy involve poorly controlled angiogenesis that is of great concern, but in our discussion, we will focus more on several alterations in the retinal circulation occurring earlier in the progression of disease, including reductions in blood flow and a possible redistribution of perfusion that may leave some areas of the retina ischemic and hypoxic. Finally, we include in this article a more recent area of investigation regarding the diabetic retinal vasculature, that is, the alterations to the endothelial surface layer that normally plays a vital role in maintaining physiological functions. © 2020 American Physiological Society. Compr Physiol 10:933-974, 2020.
... In a previous study with an experimental animal model, we previously reported that intravitreal injection of an anti-VEGF agent can attenuate the infiltration of leukocytes, especially macrophages, into the retina and can suppress preretinal neovascularization (87). Esser et al. demonstrated that inflammatory phase macrophages are localized in FVMs in PDR (88). This finding implied that macrophage-induced inflammation is associated with FVM formation. ...
In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.
... In the past decades, increasing studies have indicated that inflammation play a key role in the pathogenesis of diabetic retinopathy [3,[15][16][17]. There are many features typical of inflammation in the retina of diabetic patients and rodents, such as increased blood flow and vascular permeability [17], enhanced leukocyte adhesion and macrophage infiltration [18,19], and strengthened expression of various inflammatory mediators [15,20]. Many of those mediators have become research spots as they may stand as potential therapeutic targets for the treatment of diabetic retinopathy, IL-1β and TNF-α should be counted. ...
Background:
Cyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy.
Methods:
Male Sprague-Dawley rats were established to type 2 diabetic model. After 6 weeks, diabetic rats and normal controls were intravitreally injected with. Cs-A (42 ng/2 μL) to the left eye, and 2 μL DMSO to the right eye for the control.. Another group of normal wild-type rats was subjected to intravitreal injections into. The left eyes with 5 μL PBS or HMGB-1 (5 ng/5 μL) or HMGB-1(5 ng/5 μL) plus. Cs-A (42 ng/2 μL), respectively. Retinal morphological changes were observed with. Hematoxylin-eosin staining. Expressions of HMGB-1, IL-1β and TNF-α were. Detected by immunohistochemistry, ELISA or Western blot or RT-PCR.
Results:
Retinal expression levels of IL-1β and TNF-α were upregulated in type 2. diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were. Attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in. diabetic retina and relieved the retinopathy in type 2 diabetic rats.
Conclusions:
Intravitreal administration of Cs-A showed a protective effect on retina. of diabetic rats, possibly by downregulating retinal expressions of IL-1β and TNF-α. via the suppression of HMGB-1.
... In the past decades, increasing studies have indicated that in ammation play a key role in the pathogenesis of diabetic retinopathy [3, 16-18]. There are many features typical of in ammation in the retina of diabetic patients and rodents, such as increased blood ow and vascular permeability [18], enhanced leukocyte adhesion and macrophage in ltration[19,20], and strengthened expression of various in ammatory mediators[16,21]. Many of those mediators have become research spots as they may stand as potential therapeutic targets for the treatment of diabetic retinopathy, IL-1β and TNF-α should be counted. ...
Background:Cyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy.
Methods:Male Sprague-Dawley rats were established to type 2 diabetic model.After 6 weeks, diabetic rats and normal controls were intravitreally injected with Cs-A (42 ng/2 μL) to the left eye, and 2μL DMSO to the right eye for the control. Another part of normal wild-type rats was subjected to intravitreal injections into the left eyes with 5 μL PBS or HMGB-1 (5 ng/5 μL) or HMGB-1(5 ng/5 μL) plus Cs-A (42 ng/2 μL), respectively. Retinal morphological changes were observed with hematoxylin–eosin staining. Expressions of HMGB-1, IL-1β and TNF-α were detected by immunohistochemistry, ELISA or western blot.
Results:Retinal expression levels of IL-1β and TNF-α were upregulated in type 2 diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in diabetic retina and relieved the retinopathy in type 2 diabetic rats.
Conclusions:Intravitreal administration of Cs-A showed a protective effect on retina of diabetic rats, possibly by downregulating retinal expressions of IL-1β and TNF-α via the suppression of HMGB-1.
