Evaluation of Proteoforms of the Transmembrane Chemokines CXCL16 and CX3CL1, Their Receptors, and Their Processing Metalloproteinases ADAM10 and ADAM17 in Proliferative Diabetic Retinopathy

El‐Asrar, Ahmed M. Abu; Nawaz, Mohd Imtiaz; Ahmad, Ajmal; Zutter, Alexandra De; Siddiquei, Mohammad Mairaj; Blanter, Marfa; Allegaert, Eef; Gikandi, Priscilla W; Hertogh, Gert De; Damme, Jo Van; Opdenakker, Ghislain; Struyf, Sofie

doi:10.3389/fimmu.2020.601639

Cited by 31 publications

(50 citation statements)

References 81 publications

(158 reference statements)

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“…Angiogenesis and inflammation are the key feature of PDR and also thought to be critical mechanisms for PDR initiation and progression ( 3 , 15 ). In this study, we showed higher vitreous levels of angiogenesis and inflammation mediators including syndecan-1, PIGF, ANGPTL-4, VEGF and IL-8 in eyes with PDR.…”

Section: Discussionmentioning

confidence: 99%

Correlations Between Different Angiogenic and Inflammatory Factors in Vitreous Fluid of Eyes With Proliferative Diabetic Retinopathy

Tang

et al. 2021

Front. Med.

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Purpose: To investigate the expression of various angiogenesis and inflammation mediators in the vitreous fluid of eyes with proliferative diabetic retinopathy (PDR).Methods: A total of 38 eyes with PDR and 37 control eyes were included. Vitreous fluid was collected during vitrectomy. Vitreous levels of colony stimulating factor-1 receptor (CSF-1R), syndecan-1, placental growth factor (PIGF), and angiopoietin-like protein 4 (ANGPTL-4) were measured by multiplex immunoassay. Vitreous levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) were measured by cytometric beads array. Levels of these mediators were compared between the PDR and control eyes. Correlations between levels of different mediators and between these mediators and kidney function metrics in the PDR group were also analyzed.Results: Vitreous levels of syndecan-1, PIGF, ANGPTL-4, VEGF, and IL-8 were significantly higher in the PDR group compared to the control group (all p < 0.05). Levels of VEGF were significantly correlated with levels of syndecan-1, PIGF, and ANGPTL-4 (r = 0.370 to 0.497, all p < 0.05). Significant positive correlations were detected between levels of any two of the following mediators including syndecan-1, PIGF, ANGPTL-4, and IL-8 (r = 0.370 to 0.906, all p < 0.05). Apart from VEGF, levels of these mediators were positively correlated with serum creatinine and blood urea nitrogen (r = 0.328 to 0.638, all p < 0.05), and negatively correlated with fasting blood glucose and estimated glomerular filtration rate (r = −0.325 to −0.603, all p < 0.05).Conclusions: Correlations between different angiogenesis and inflammation mediators were observed in eyes with PDR, suggesting cross-talks of different angiogenesis and inflammation pathways in the pathogenesis of PDR. The levels of angiogenesis and inflammation in PDR are correlated with kidney damage, indicating possible common pathways in diabetic retinopathy and nephropathy.

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Section: Discussionmentioning

confidence: 99%

Correlations Between Different Angiogenic and Inflammatory Factors in Vitreous Fluid of Eyes With Proliferative Diabetic Retinopathy

Tang

et al. 2021

Front. Med.

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“…12 Our hypothesis-driven approach identified PDGF as a major inducer of neurite outgrowth, but this does not exclude that other growth factors and cytokines may also play an important role in neurite outgrowth in PDR. For example, two recent studies showed the involvement of the chemokine axis CXCL16/CXCR6 and the metalloproteinases ADAM10 and ADAM17 30 and the involvement of CD146 31 in vitreous of PDR patients, FVMs and in Müller cell activation.…”

Section: Discussionmentioning

confidence: 99%

PDGF as an Important Initiator for Neurite Outgrowth Associated with Fibrovascular Membranes in Proliferative Diabetic Retinopathy

Lefevere

Hove

Sergeys

et al. 2021

Current Eye Research

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Purpose:The formation of fibrovascular membranes (FVMs) is a serious sight-threatening complication of proliferative diabetic retinopathy (PDR) that may result in retinal detachment and eventual blindness. During the formation of these membranes, neurite/process outgrowth occurs in retinal neurons and glial cells, which may both serve as a scaffold and have guiding or regulatory roles. To further understand this process, we investigated whether previously identified candidate proteins, from vitreous of PDR patients with FVMs, could induce neurite outgrowth in an experimental setting. Materials and methods: Retinal explants of C57BL6/N mouse pups on postnatal day 3 (P3) were cultured in poly-L-lysine-and laminin-coated dishes. Outgrowth stimulation experiments were performed with the addition of potential inducers of neurite outgrowth. Automated analysis of neurite outgrowth was performed by measuring β-tubulin-immunopositive neurites using Image J. Expression of PDGF receptors was quantified by RT-PCR in FVMs of PDR patients. Results: Platelet-derived growth factor (PDGF) induced neurite outgrowth in a concentration-dependent manner, whilst neuregulin 1 (NRG1) and connective tissue growth factor (CTGF) did not. When comparing three different PDGF dimers, treatment with PDGF-AB resulted in the highest neurite induction, followed by PDGF-AA and -BB. In addition, incubation of retinal explants with vitreous from PDR patients resulted in a significant induction of neurite outgrowth as compared to non-diabetic control vitreous from patients with macular holes, which could be prevented by addition of CP673451, a potent PDGF receptor (PDGFR) inhibitor. Abundant expression of PDGF receptors was detected in FVMs. Conclusion:Our findings suggest that PDGF may be involved in the retinal neurite outgrowth, which is associated with the formation of FVMs in PDR.

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“…CX3CL1 is a membrane-bound chemokine, which functions as an adhesion molecule for leukocytes, but can also be proteolytically cleaved, resulting in a soluble form with chemotactic function (97, 98). Several studies already demonstrated the implication of CX3CL1 in DR pathogenesis as the vitreous of PDR patients contains elevated levels of CX3CL1 (99) Furthermore, circulating CD11b+ leukocytes that are involved in leukostasis in DR express higher levels of CX3CR1 in diabetic mice compared to controls (100). Thus, membrane-bound CX3CL1 on the surface of Müller cells might be involved in leukostasis in DR.…”

Section: Discussionmentioning

confidence: 99%

Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity

Schmalen

Lorenz

Grosche

et al. 2021

Preprint

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Mueller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Mueller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Mueller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Mueller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Mueller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Mueller cells and the human Mueller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Mueller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Mueller cells results in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Mueller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Mueller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation underlying the pathogenesis of diabetic retinopathy.

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Evaluation of Proteoforms of the Transmembrane Chemokines CXCL16 and CX3CL1, Their Receptors, and Their Processing Metalloproteinases ADAM10 and ADAM17 in Proliferative Diabetic Retinopathy

Cited by 31 publications

References 81 publications

Correlations Between Different Angiogenic and Inflammatory Factors in Vitreous Fluid of Eyes With Proliferative Diabetic Retinopathy

Correlations Between Different Angiogenic and Inflammatory Factors in Vitreous Fluid of Eyes With Proliferative Diabetic Retinopathy

PDGF as an Important Initiator for Neurite Outgrowth Associated with Fibrovascular Membranes in Proliferative Diabetic Retinopathy

Proteomic phenotyping of stimulated Müller cells uncovers profound pro-inflammatory signaling and antigen-presenting capacity

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