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IL-1β is upregulated in the diabetic retina and retinal vessels: cell-specific effect of high glucose and IL-1β autostimulation.

ABSTRACT: Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1β-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1β is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1β has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1β overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1β itself on IL-1β expression in microglial, macroglial (astrocytes and Müller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1β in isolated retinal vessels and on the temporal pattern of IL-1β upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1β was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, α2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1β expression in retinal endothelial cells but not in macroglia and microglia. IL-1β induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1β overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1β expression as compared to non-diabetic rats. Retinal expression of IL-1β increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1β in diabetes; and to IL-1β itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1β overexpression. Interrupting the vicious circle triggered by IL-1β autostimulation could limit the progression of diabetic retinopathy.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3353989 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:In diabetic macular edema (DME), identification of baseline markers on spectral-domain optical coherence tomography (SD-OCT) and their association with severity of diabetic retinopathy (DR) might aid in disease management and the design of future trials. Objective:To examine associations between DR severity, retinal morphology on SD-OCT, and visual acuity in participants with DME. Design, Setting, and Participants:This cross-sectional observational case series was conducted at a single tertiary care referral center. Demographics, visual acuity, SD-OCT, and color fundus photographs of 80 individuals with DME (102 eyes) seen between December 28, 2013, and April 30, 2014, were analyzed between May 1 and July 31, 2016. Main Outcomes and Measures:Features captured on SD-OCT and thickness metrics. On SD-OCT we graded type and shape of DME, shape and presence of septae within the intraretinal cystoid abnormalities, presence of hyperreflective dots and foci, integrity of the external limiting membrane and ellipsoid zone, presence and extent of disorganization of the inner retinal layers (DRIL), and the status of the vitreomacular interface and epiretinal membrane. We measured retinal thickness at the fovea and at the site of maximum pathology, choroidal thickness at the fovea, and 1000 ?m temporal and nasal to the fovea. Color photographs were graded to derive a DR severity stage. Results:The mean (SD) age was 63 (11) years, and 30 participants (37.5%) were women. The odds of having DRIL were greater in eyes with disrupted external limiting membrane (odds ratio [OR], 4.4; 95% CI, 1.6-12.0; P?=?.003), disrupted ellipsoid zone (OR, 2.7; 95% CI, 1.0-7.2; P?=?.03), presence of epiretinal membrane (OR, 2.8; 95% CI, 1.0-7.4; P?=?.03), and increase in retinal thickness at the fovea (OR, 1.6; 95% CI, 1.1-2.2; P?<?.001). Occurrence of DRIL was more likely in eyes with proliferative DR (OR, 7.3; 95% CI, 1.7-31.4; P?=?.007). Mean visual acuity decreased by approximately 4.7 letters for each 100-?m increase in the average global DRIL (95% CI, -7.9 to 1.4; P?=?.006). Conclusions and Relevance:An association was found between DRIL and disruption of the outer retina and increasing DR severity. Further longitudinal studies seem warranted to determine whether DRIL is a clinically relevant noninvasive morphological marker in eyes with DME.

Project description:Interleukin-1β (IL-1β) is one of the most potent pro-inflammatory cytokines implicated in a wide range of autoinflammatory, autoimmune, infectious, and degenerative diseases. Therefore, many researchers have focused on developing therapeutic molecules that inhibit IL-1β-IL-1 receptor 1 (IL-1R1) interaction for the treatment of IL-1-related diseases. Among IL-1-related diseases, osteoarthritis (OA), is characterized by progressive cartilage destruction, chondrocyte inflammation, and extracellular matrix (ECM) degradation. Tannic acid (TA) has been proposed to have multiple beneficial effects, including anti-inflammatory, anti-oxidant, and anti-tumor activities. However, it is unclear whether TA plays a role in anti-IL-1β activity by blocking IL-1β-IL-1R1 interaction in OA. In this study, we report the anti-IL-1β activity of TA in the progression of OA in both in vitro human OA chondrocytes and in vivo rat OA models. Herein, using-ELISA-based screening, natural compound candidates capable of inhibiting the IL-1β-IL-1R1 interaction were identified. Among selected candidates, TA showed hindering IL-1β-IL-1R1 interaction by direct binding to IL-1β using surface plasmon resonance (SPR) assay. In addition, TA inhibited IL-1β bioactivity in HEK-Blue IL-1-dependent reporter cell line. TA also inhibited IL-1β-induced expression of inducible nitric oxide synthase (NOS2), cyclooxygenase-2 (COX-2), IL-6, tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in human OA chondrocytes. Moreover, TA downregulated IL-1β-stimulated matrix metalloproteinase (MMP)3, MMP13, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)4, and ADAMTS5, while upregulating collagen type II (COL2A1) and aggrecan (ACAN). Mechanistically, we confirmed that TA suppressed IL-1β-induced MAPK and NF-κB activation. The protective effects of TA were also observed in a monosodium iodoacetamide (MIA)-induced rat OA model by reducing pain and cartilage degradation and inhibiting IL-1β-mediated inflammation. Collectively, our results provide evidence that TA plays a potential role in OA and IL-1β-related diseases by hindering IL-1β-IL-1R1 interaction and suppressing IL-1β bioactivity.

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IL-1β is upregulated in the diabetic retina and retinal vessels: cell-specific effect of high glucose and IL-1β autostimulation.

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