Mesenchymal Stem Cell Exosomal miR-146a Mediates the Regulation of the TLR4/MyD88/NF-κB Signaling Pathway in Inflammation due to Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is the main cause of vision loss in diabetic patients, which cannot be completely resolved by typical blood sugar control. Inflammation influences the development of DR, so reducing the inflammatory response in DR patients is crucial to the prevention of DR. Therefore, we explored the regulatory effect of bone marrow mesenchymal stem cell (BMSC) exosomes on inflammation in DR mice. In order to analyze the mechanism of action, we used BMSC exosomal miR-146a to treat microglias in DR mice to observe cellular changes and expression of inflammatory factors. It was found that BMSC exosomal miR-146a reduced the levels of proliferating cell antigen and B-cell lymphoma-2 in microglias of DR mice and increased Bcl-2-related X with cysteine aspartic protease-3. By analyzing the expression of inflammatory factors, we found that BMSC exosomal miR-146a reduced the levels of TNF-α, IL-1β, and IL-6, which suggested that miR-146a can alleviate inflammation in DR mice. Further exploration found that miR-146a reduced the activity of TLR4 and increased the activity of MyD88 and NF-κB. Furthermore, the overexpression of TLR4 reversed the effects of miR-146a on the proliferation, apoptosis, and inflammation of microglias. Our study demonstrated that BMSC exosomal miR-146a can regulate the inflammatory response of DR by mediating the TLR4/MyD88/NF-κB pathway, providing an experimental basis for the prevention and treatment of DR.

Advances in Research Related to MicroRNA for Diabetic Retinopathy

“…Li et al [203] found that miR-486-3p can be induced within mesenchymal stem cells of bone marrow to generate exosomes, and TLR4 is a target of miR-486-3p, suggesting that there is a link between miR-486-3p and DR disease pathology. In this study, they showed that positive regulation of miR-486-3p can downregulate TLR4, thus inhibiting Cao et al [204] found that the secretion of bone marrow mesenchymal stem cell miR-146a reduced TNF-α and the levels of IL-1 and IL-6, suggesting that miR-146a can reduce the inflammatory response in DR mice. Further research has found that miR-146a can reduce the activity of TLR4.…”

“…Cao et al [ 204 ] found that the secretion of bone marrow mesenchymal stem cell miR-146a reduced TNF- α and the levels of IL-1 and IL-6, suggesting that miR-146a can reduce the inflammatory response in DR mice. Further research has found that miR-146a can reduce the activity of TLR4.…”

Exosomes derived from BMSCs alleviates high glucose‐induced diabetic retinopathy via carrying miR‐483‐5p

“…Meanwhile, Gu et al suggested that BMSCs‐derived exosomes could alleviate the progression of DR through carrying miR‐146a. [ 23 ] MiR‐146a was reported to be the anti‐inflammatory factor in the progression of diabetes, [ 24 ] and miR‐483‐5p was also known as an anti‐inflammatory factor. [ 25,26 ] Thus, the similar function between miR‐483‐5p and miR‐146a might contribute to the similarity between our study and Gu et al…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications

“…The knockdown of NEDD4 significantly impairs the retinal protective potential of MSC-EVs. In addition, the miRNAs in MSC-EVs such as miR-18b, miR-17-3p, miR-486-3p, miR-146a, miR-192, and miR-133b-3p also exert repairing roles to promote the recovery of retinal function and structure [ 96 , 97 , 98 , 99 , 100 , 101 ]. Furthermore, MSC-EVs are reported to carry brain-derived neurotrophic factor (BDNF) to retinal neurons of diabetic rats and inhibit neuronal apoptosis by activating the TrkB pathway [ 102 ].…”