CD40 Upregulation in the Retina of Patients With Diabetic Retinopathy: Association With TRAF2/TRAF6 Upregulation and Inflammatory Molecule Expression

Vos, Sarah C.; Aaron, Rachel V.; Weng, M.H.; Daw, Jad; Rodríguez-Rivera, E.; Subauste, Carlos S.

doi:10.1167/iovs.64.7.17

Cited by 6 publications

(6 citation statements)

References 65 publications

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“…CD40 expressed in Müller cells plays a central role in the induction of inflammatory responses and the development of diabetic retinopathy [ 3 ]. Moreover, the expression of CD40 in Müller cells is increased in mice and patients with diabetic retinopathy [ 2 , 6 ]. We examined the effect of MGO-modified fibronectin on the expression of CD40 in Müller cells.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…The expression of CD40 is elevated in endothelial and Müller cells in the retinas from patients with diabetic retinopathy [ 6 ]. Moreover, areas of increased CD40 expression co-localize with pro-inflammatory molecules (ICAM-1 in endothelial cells and CCL2 in Müller cells) [ 6 ]. To assess the in vivo relevance of AGEs in CD40 upregulation, we examined AGE-induced protein modification and CD40 expression in posterior poles from patients with diabetic retinopathy.…”

Section: Resultsmentioning

confidence: 99%

“…Images were processed in Photoshop CC 19.1.1. using similar linear adjustments for all samples. Semiquantitative assessment of CML and CD40 expression was performed using MetaMorph (Nashville, TN, USA) [ 6 ]. Briefly, areas positive for von Willebrand factor and fibronectin or vimentin and laminin were identified.…”

Section: Methodsmentioning

confidence: 99%

“…CD40 expression is elevated in endothelial cells and retinal Müller cells from mice and humans with diabetic retinopathy [ 2 , 6 ]. Moreover, a modest upregulation of CD40 causes a marked increase in CD40-driven pro-inflammatory responses in vitro [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy

Portillo,

Pfaff,

Vos

et al. 2024

Cells

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CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven inflammatory disorders. What drives CD40 upregulation in the diabetic retina remains unknown. We examined the role of advanced glycation end products (AGEs) in CD40 upregulation in endothelial cells and Müller cells. Human endothelial cells and Müller cells were incubated with unmodified or methylglyoxal (MGO)-modified fibronectin. CD40 expression was assessed by flow cytometry. The expression of ICAM-1 and CCL2 was examined by flow cytometry or ELISA after stimulation with CD154 (CD40 ligand). The expression of carboxymethyl lysine (CML), fibronectin, and laminin as well as CD40 in endothelial and Müller cells from patients with DR was examined by confocal microscopy. Fibronectin modified by MGO upregulated CD40 in endothelial and Müller cells. CD40 upregulation was functionally relevant. MGO-modified fibronectin enhanced CD154-driven upregulation of ICAM-1 and CCL2 in endothelial and Müller cells. Increased CD40 expression in endothelial and Müller cells from patients with DR was associated with increased CML expression in fibronectin and laminin. These findings identify AGEs as inducers of CD40 upregulation in endothelial and Müller cells and enhancers of CD40-dependent pro-inflammatory responses. CD40 upregulation in these cells is associated with higher CML expression in fibronectin and laminin in patients with DR. This study revealed that CD40 and AGEs, two important drivers of DR, are interconnected.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy

Portillo,

Pfaff,

Vos

et al. 2024

Cells

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Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies

Strohm,

Daiber,

Ubbens

et al. 2024

Basic Res Cardiol

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CD40L–CD40–TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L–CD40–TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L–CD40–TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L–CD40–TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.

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Identification of a novel peptide with anti-inflammatory activity from Binglangjiang buffalo fermented milk and its potential inhibitory mechanism in lipopolysaccharide-stimulated RAW264.7 cells

Zheng,

Li,

Wang

et al. 2025

Food Chemistry

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CD40 Upregulation in the Retina of Patients With Diabetic Retinopathy: Association With TRAF2/TRAF6 Upregulation and Inflammatory Molecule Expression

Cited by 6 publications

References 65 publications

Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy

Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy

Role of inflammatory signaling pathways involving the CD40–CD40L–TRAF cascade in diabetes and hypertension—insights from animal and human studies

Identification of a novel peptide with anti-inflammatory activity from Binglangjiang buffalo fermented milk and its potential inhibitory mechanism in lipopolysaccharide-stimulated RAW264.7 cells

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