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IL-6 signaling. IL-6 activates cellular signaling using either cis-(reliant on expression of cell surface receptor) or trans-(via soluble IL-6 receptor) mechanisms. Both mechanisms require expression of the coreceptor gp130 and lead to activation of the Jak-STAT3 and Ras-MEK-ERK-AP1(Fos + Jun) signaling pathways. STAT3 activity promotes expression of VEGF-A, inflammatory mediators, and disruption of the endothelial barrier, whilst Fos+Jun promote expression of matrix metalloproteases. Together, these effects can cause multiple sequelae of diabetic retinopathy
Source publication
Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal v...
Context in source publication
Context 1
... of IL-6R (sIL-6R) can also bind IL-6 and form a complex with gp130 subunits in cells that lack the transmembrane IL-6R, a process known as IL-6 trans-signaling [95]. Both modes of IL-6R signaling lead to gp130 activation of Jak1, Jak2, and Tyk2, which in turn induces phosphorylation of STAT1 and STAT3 as well as activation of the MAPK cascades (Fig. 6). It has been hypothesized that IL-6 responses via the membrane-bound IL-6R are rather protective and regenerative whereas IL-6 trans-signaling appears to be involved in the pro-inflammatory activities of this cytokine ...
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Citations
... Chronic inflammation is a key factor in retinal diseases, including DME and AMD. 27,28 The correlation between intraocular IL-6 levels and visual acuity (VA) outcomes with ranibizumab treatment in the HARBOR and READ-3 trials was examined. In the HARBOR trial, there was no correlation between AH and serum IL-6 concentrations, suggesting local intraocular secretion. ...
Background: DME and AMD are major causes of blindness, affecting the macula and central vision. AMD accounts for 8.7 of global blindness cases. Understanding AMD beyond the retina can provide insights into its pathophysiology, consequences, therapy, and clinical course. Anti-VEGF agents have shown promise in treating AMD, but a definitive treatment remains unidentified. Methods: Following PRISMA 2020 guidelines, this systematic review concentrated on full-text English literature published between 2014 and 2024. Editorials and review articles that appeared in the same journal as the submission were not accepted without a DOI. A number of websites, including ScienceDirect, PubMed, and SagePub, were utilized to gather the literature. Result: The study looked at more than 400 publications using reputable sources including Science Direct, SagePub, and PubMed. After it was decided that eight publications needed greater investigation, a more extensive review of the entire literature was carried out. Conclusion: BCVA is crucial in the treatment of AMD and DME, with targeting VEGF being an effective approach. However, their effectiveness in other forms of AMD is less convincing. Chronic inflammation is a key factor in retinal diseases, including AMD. DME treatment requires a multidisciplinary approach, with anti-VEGF agents being the first-line treatment.
... Some studies also suggest that IL-1 inhibitor treatment may reduce the risk of macrovascular and microvascular complications of diabetes [95,96]. IL-1 receptor antagonist Anakinra and monoclonal antibody-mediated suppression of IL-1β with canakinumab had similar effects in other trials [16,97,98]. ...
Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.
... Actually, the person who has DM contains higher possibilities of DR [4]. Especially, pregnant women with DM are having more chance to affect by the effects of DR [5]. ...
One of the common diseases in people with micro aneurysms is diabetic retinopathy (DR). Due to a lack of early diagnosis, diabetic retinopathy poses a risk to vision because it develops without any warning symptoms. Therefore, the deep learning methods on color fundus images demonstrate the recognition task of diabetic retinopathy levels. In this manuscript, an automated Micro aneurysm detection and classification utilizing deep convolution spike neural network (DCSNN-AMA) is proposed for diabetic retinopathy. Here, the images are filtered using Savitzky-Golay (SG) pre-processing method. After preprocessing, the images are segmented under Tsalli's Entropy based multilevel 3D Otsu (TE-3D-Otsu) thresholding technique. The images are extracted under Gray level co-occurrence matrix (GLCM) window adaptive algorithm operation. After that, the Deep Convolutional Spiking Neural Network (DCSNN) method is employed for classification. The proposed method has attained 32.5, 19 and 24.4% higher accuracy, 23, 31.6 and 24.4% higher F-measure, and 19.35, 8 and 16.12% lower computation time analyzed to the existing models.
... One research found in AD transgenic mice, retinal inflammation was observed to be activated [9], which can disrupt BRB and impair normal visual function [34,35]. The deposition of Aβ 1-42 could activate NLRP3 inflammasomes and induce the production of inflammatory cytokines in mice [18]. ...
Neuroinflammation and endothelial cell apoptosis are prominent features of blood–brain barrier (BBB) disruption, which have been described in Alzheimer’s disease (AD) and can predict cognitive decline. Recent reports revealed vascular β-amyloid (Aβ) deposits, Muller cell degeneration and microglial dysfunction in the retina of AD patients. However, there has been no in-depth research on the roles of inflammation, retinal endothelial cell apoptosis, and blood-retinal barrier (BRB) damage in AD retinopathy. We found that Raddeanin A (RDA) could improve pathological and cognitive deficits in a mouse model of Alzheimer’s disease by targeting β-amyloidosis, However, the effects of RDA on AD retinal function require further study. To clarify whether RDA inhibits inflammation and apoptosis and thus improves BRB function in AD-related retinopathy. In vitro we used Aβ-treated HRECs and MIO-M1 cells, and in vivo we used 3×Tg-AD mice to investigate the effect of RDA on BRB in AD-related retinopathy. We found that RDA could improve BRB function in AD-related retinopathy by inhibiting NLRP3-mediated inflammation and suppressing Wnt/β-catenin pathway-mediated apoptosis, which is expected to improve the pathological changes in AD-related retinopathy and the quality of life of AD patients.
... To the best of our knowledge, this is the first network meta-analysis that evaluated the role of chemokines in diabetic eye disease. Previous studies have shown that various chemokines and their mediated immune microenvironment may be associated with diabetic eye disease [26,27]. The challenge for these studies was that it was difficult to confirm this association in individual studies due to limited sample size. ...
... Future studies need to further explore the role of chemokines in other diabetic eye diseases including PVR, CME, SRD, CRVO and DRT. Although the mechanism by which hyperglycemia causes retinopathy progression is not fully understood, studies have shown that chemokines may be involved in multiple pathways of retinopathy, including nuclear-factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, oxidative stress, dysregulation of reactive oxygen species (ROS) and nitric oxide synthase (NOS), activation of signal transducers and activators of transcription proteins (STATs), and formation of advanced glycation end-products (AGEs) [26][27][28]. These pathways could lead to osmotic vascular damage and retinopathy by activation of mitogen activated protein kinases (MAPKs), inducing the production of ICAM-1 and VCAM-1, and the breakdown of the vascular junction proteins [11,29]. ...
Background
Diabetic eye disease is a common micro-vascular complication of diabetes and a leading cause of decreased vision and blindness in people of working age worldwide.Although previous studies have shown that chemokines system may be a player in pathogenesis of diabetic eye disease, it is unclear which chemokines play the most important role.To date, there is no meta-analysis which has investigated the role of chemokines in diabetic eye disease.We hope this study will contribute to a better understanding of both the signaling pathways of the chemokines in the pathophysiological process, and more reliable therapeutic targets for diabetic eye disease.
Methods
Embase, PubMed, Web of Science and Cochrane Library systematically searched for relevant studies from inception to Sep 1, 2023. A random-effect model was used and standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated to summarize the associated measure between chemokines concentrations and diabetic eye disease. Network meta-analysis to rank chemokines-effect values according to ranked probabilities.
Results
A total of 33 different chemokines involving 11,465 subjects (6559 cases and 4906 controls) were included in the meta-analysis. Results of the meta-analysis showed that concentrations of CC and CXC chemokines in the diabetic eye disease patients were significantly higher than those in the controls. Moreover, network meta-analysis showed that the effect of CCL8, CCL2, CXCL8 and CXCL10 were ranked highest in terms of probabilities. Concentrations of CCL8, CCL2, CXCL8 and CXCL10 may be associated with diabetic eye disease, especially in diabetic retinopathy and diabetic macular edema.
Conclusion
Our study suggests that CCL2 and CXCL8 may play key roles in pathogenesis of diabetic eye disease. Future research should explore putative mechanisms underlying these links, with the commitment to develop novel prophylactic and therapeutic for diabetic eye disease.
... There is mounting evidence that chronic inflammation plays a key role in the pathogenesis of retinal diseases, including nAMD and DMO [26][27][28]. There are numerous reports of increased concentrations of the pro-inflammatory cytokine IL-6 in the AH and vitreous humour of patients with nAMD and DMO [7-10, 16, 17, 23]. ...
Background
This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti–vascular endothelial growth factor (VEGF) monotherapy.
Methods
Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12. Main outcome measure: association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA).
Results
In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (−2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of −9.0 (−22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters.
Conclusions
Higher IL-6 AH concentrations may predict suboptimal visual responses to anti–VEGF monotherapy in patients with nAMD/DMO.
... Neuroinflammation has been identified as a critical key factor in both the initiation onset and progression of DR [17]. Abnormal expression levels of ubiquitination are also important in the development of DR [18,19]. ...
Diabetic retinopathy (DR) is a diabetes-associated complication that poses a threat to vision, distinguished by persistent and mild inflammation of the retinal microvasculature. The activation of microglia plays a crucial role in driving this pathological progression. Previous investigations have demonstrated that ubiquitin-specific peptidase 25 (USP25), a deubiquitinating enzyme, is involved in the regulation of immune cell activity. Nevertheless, the precise mechanisms through which USP25 contributes to the development of DR remain incompletely elucidated. Firstly, we have demonstrated the potential mechanism by which ROCKs can facilitate microglial activation and augment the synthesis of inflammatory mediators through the modulation of NF-κB signaling pathways in a high-glucose milieu. Furthermore, our study has provided novel insights by demonstrating that the regulatory role of USP25 in the secretion of proinflammatory factors is mediated through the involvement of ROCK in modulating the expression of NF-κB and facilitating the nuclear translocation of the phosphatase NF-κB. This regulatory mechanism plays a crucial role in modulating the activation of microglial cells within a high-glycemic environment. Hence, USP25 emerges as a pivotal determinant for the inflammatory activation of microglial cells, and its inhibition exhibits a dual effect of promoting retinal neuron survival while suppressing the inflammatory response in the retina. In conclusion, the promotion of diabetic retinopathy (DR) progression by USP25 is attributed to its facilitation of microglial activation induced by high glucose levels, a process mediated by the ROCK pathway. These findings highlight the importance of considering USP25 as a potential therapeutic target for the management of diabetic neuroinflammation.
... We compared the roles of macrophages and M1 microglia in mediating inflammation (Fig. 2F). Similar to M1 microglia, macrophages secrete inflammatory factors (Il1β and Il12) [71,72] and express NAPDH oxidases involved in oxidative stress, such as Rac2, Cybb and Ncf4 [73,74]. However, the ability of macrophages to promote inflammation is weaker than that of M1 microglia. ...
... Then, we constructed a PPI network for the proteins highly expressed by macrophages (Fig. 5A). We found that these proteins (Il1β, Ccl3, Cxcr4, Rac2, and Laptm5) [71,73,[76][77][78] were important in the protein interaction networks. KEGG analysis suggested that the MAPK, PI3K-Akt and Ras signaling pathways were upregulated in macrophages, which may be related to adhesion aggregation and chemokine release [52,79,80] (Fig. 5B). ...
... Adhesion and aggregation of inflammatory cells lead to microvascular leakage in early DR by releasing inflammatory factors and disrupting the BRB [71,83]. Our research also shows that inflammatory cells enhance damage to the BRB through adhesion and aggregation, release of matrix metalloproteases (MMPs) and enhancement of oxidative stress. ...
Background
The pathophysiological mechanisms of diabetic retinopathy (DR), a blinding disease, are intricate. DR was thought to be a microvascular disease previously. However, growing studies have indicated that the retinal microglia-induced inflammation precedes microangiopathy. The binary concept of microglial M1/M2 polarization paradigms during inflammatory activation has been debated. In this study, we confirmed microglia had the most significant changes in early DR using single-cell RNA sequencing.
Methods
A total of five retinal specimens were collected from donor SD rats. Changes in various cells of the retina at the early stage of DR were analyzed using single-cell sequencing technology.
Results
We defined three new microglial subtypes at cellular level, including two M1 types (Egr2⁺ M1 and Egr2⁻ M1) and one M2 type. We also revealed the anatomical location between these subtypes, the dynamic changes of polarization phenotypes, and the possible activation sequence and mutual activation regulatory mechanism of different cells. Furthermore, we constructed an inflammatory network involving microglia, blood-derived macrophages and other retinal nonneuronal cells. The targeted study of new disease-specific microglial subtypes can shorten the time for drug screening and clinical application, which provided insight for the early control and reversal of DR.
Conclusions
We found that microglia show the most obvious differential expression changes in early DR and reveal the changes in microglia in a high-glucose microenvironment at the single-cell level. Our comprehensive analysis will help achieve early reversal and control the occurrence and progression of DR.
... The pathogenesis of DR is complex, mainly involving retinal microangiopathy (blood flow changes, blood-retinal barrier dysfunction, Capillary endothelial cell death), inflammation, oxidative stress, polyol pathway, hexosamine pathway, cytokines, reninangiotensin system, etc [37][38][39]. CPMs are produced based on traditional Chinese medicine theory combined with modern biotechnology, DS, QM and XST have been widely used in the treatment of DR in China. The main components of DS are Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and borneol, which can improve local blood circulation, protect vascular endothelial cells, and achieve the purpose of eliminating congestion [40,41]. ...
Objectives
Chinese patent medicines (CPMs) are commonly prescribed by clinicians in China as adjuvant therapy for diabetic retinopathy (DR). The study of network meta-analysis (NMA) aims to compare the effectiveness and safety of three CPMs plus calcium dobesilate (CD) for DR, and to explore optimal CPM for treatment of DR. Methods. Bayesian network meta-analyses were designed to evaluate the safety and effectiveness of different CPMs for the treatment of DR. Systematic Review Registration CRD42022323996. Results. A total of 23 eligible RCTs involving 1824 patients were enrolled. Compared with CD alone, Cmpound Danshen Dripping Pills (DS) + CD or Qiming Granule (QM) + CD considerably enhanced best corrected visual acuity (BCVA); DS + CD or Compound Xueshuantong Capsule (XST) + CD significantly reduced macular thickness; CPMs + CD significantly reduced the level of VEGF. In addition, DS + CD or XST + CD over QM + CD in reducing macular thickness. As for the adverse events, the differences across different CPMs were not statistically significant, and no statistically significant difference between the CPMs and CD. Conclusion. DS plus CD or QM plus CD may be better effective in improving BCVA; DS plus CD or XST plus CD may be better effective in reducing macular thickness; The combination therapy all may be better effective in reducing the level of VEGF. As for safety profile that CPMs plus CD did not increase the incidence of adverse events. The results of this study might support DS as a relatively prior adjuvant therapy option for patients with DR.
... Leukocyte activation, leukostasis, and inflammatory cytokines secretion contribute to the development of DR. [14][15][16][17] However, the specific interactions, signaling pathways, and molecular mechanisms underlying the role of circulating immune cells in DR pathogenesis remain elusive. Unraveling these mechanisms holds immense potential for developing novel therapeutic strategies for DR and improving our understanding of other diabetic complications. ...
This study focused on examining the exact role of circulating immune cells in the development of diabetic retinopathy (DR). In vitro co-culture experiments showed that peripheral blood mononuclear cells (PBMCs) from patients with type 1 DR crucially modulated the biological functions of human retinal microvascular endothelial cells (HRMECs), consequently disrupting their normal functionality. Single-cell RNA sequencing (scRNA-seq) study revealed unique differentially expressed genes and pathways in circulating immune cells among healthy controls, non-diabetic retinopathy (NDR) patients, and DR patients. Of significance was the observed upregulation of JUND in each subset of PBMCs in patients with type 1 DR. Further studies showed that downregulating JUND in DR patient-derived PBMCs led to the amelioration of HRMEC dysfunction. These findings highlighted the notable alterations in the transcriptomic patterns of circulating immune cells in type 1 DR patients and underscored the significance of JUND as a key factor for PBMCs in participating in the pathogenesis of DR.
