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MiR-30a Regulates S100A12-induced Retinal Microglial Activation and Inflammation by Targeting NLRP3
1Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Abstract:
Purpose: Our previous study has identified that plasma levels of S100A12 are closely associated with presence and severity of diabetic retinopathy (DR). In this work, we explored whether S100A12 can contribute to retinal microglial activation and inflammatory changes of DR via a microRNA-dependent mechanism.Material and Methods: Streptozotocin (STZ)-induced DR model was developed. Retinal microglia of rats were activated through intravitreal injection of S100A12. Differential expression of miRNAs on retinal microglia treated with S100A12 or DMEM/F-12 alone was determined using microarray analysis. Luciferase reporter assays were performed, which explored the regulation of a putative target of miR-30a.Results: S100A12 was increased approximately fivefold in the retina of 16-week diabetic rats compared with nondiabetic retinas. Furthermore, the levels of NLRP3, ASC, caspase-1, IL-1β, and IL-18 were significantly increased in the retina of rats treated with intravitreal injection of S100A12. Moreover, S100A12 induced an increased expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18 in a dose- and time-dependent manner in retinal microglia. S100A12 was a proinflammatory trigger in diabetes-induced retinal microglial activation by activating NLRP3 in vivo and in vitro. In addition, S100A12 induced retinal microglial activation via a miR-30a-dependent mechanism. Mechanistically, S100A12 inhibited miR-30a expression, which was controlled by HDAC, and miR-30a downregulated NLRP3 expression by directly targeting its 3'-UTR.Conclusions: S100A12 plays an important role in the pathogenesis of DR by activating retinal microglia via a miR-30a-dependent mechanism.
Insights
Plasma levels of S100A12 protein are linked to diabetic retinopathy (DR). This study shows S100A12 activates retinal microglia via miR-30a, contributing to DR inflammation.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Plasma S100A12 levels correlate with diabetic retinopathy (DR) presence and severity.
- Diabetic retinopathy involves retinal microglial activation and inflammation.
- MicroRNA (miRNA)-dependent mechanisms may mediate S100A12's role in DR pathogenesis.
Purpose of the Study:
- To investigate if S100A12 contributes to retinal microglial activation in DR.
- To explore the role of a microRNA-dependent mechanism in S100A12-induced DR inflammation.
- To elucidate the molecular pathway linking S100A12, microglial activation, and DR.
Main Methods:
- Established a streptozotocin (STZ)-induced diabetic retinopathy (DR) rat model.
- Activated rat retinal microglia via intravitreal injection of S100A12.
- Utilized microarray analysis for differential miRNA expression and luciferase reporter assays to confirm miRNA-target interactions.
Main Results:
- S100A12 levels were significantly elevated in diabetic rat retinas.
- S100A12 induced dose- and time-dependent increases in NLRP3 inflammasome components (NLRP3, ASC, caspase-1) and inflammatory cytokines (IL-1β, IL-18) in retinal microglia.
- S100A12 inhibited miR-30a expression, which in turn downregulated NLRP3 by targeting its 3'-UTR, demonstrating a miR-30a-dependent mechanism.
Conclusions:
- S100A12 acts as a proinflammatory trigger in diabetes-induced retinal microglial activation.
- The study identifies a novel S100A12-miR-30a-NLRP3 axis in the pathogenesis of diabetic retinopathy.
- Targeting the S100A12/miR-30a pathway may offer therapeutic strategies for diabetic retinopathy.
