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Adipose tissue macrophages-derived exosomal MiR-500a-5p under high glucose promotes adipocytes inflammation by
Yong-Zhen Li1, Yuan Tian2, Chen Yang3
1Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan province, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China; Department of Pathology, The First People's Hospital of Zigong, Zigong 643099, PR China.
Background:
Type 2 diabetes (T2DM) is a chronic metabolic disorder characterized by insulin resistance and chronic inflammation. Adipose tissue macrophages (ATMs), central players in mediating pro-inflammatory responses within adipose tissue, have been shown to influence insulin sensitivity through exosome secretion. While the role of macrophages-derived exosomal miRNA has been studied in various diseases, their pathogenic roles in T2DM, particularly ATMs-derived exosomal miRNA in adipose tissue inflammation, remain underexplored.
Objectives:
This study focuses specifically on T2DM, investigating the role of ATM-derived exosomal miRNAs in adipose tissue inflammation, a critical factor in the pathogenesis of T2DM.
Methods:
ATM were isolated from visceral adipose tissues in patients with or without diabetes. Differentially expressed miRNAs in ATM-derived exosomes were predicted by high-throughput RNA sequencing. The RAW264.7 macrophages and 3T3-L1 preadipocytes was selected as a model system. Quantitative RT-PCR was used to assess miR-500a-5p expression. The direct binding of miR-500a-5p to Nrf2 mRNA 3' UTR was verified by dual luciferase assay.
Results:
MiR-500a-5p was also enriched in the exosomes of high-glucose-treated macrophages. Furthermore, these exosomes induced high expression of miR-500a-5p and activation of the NLRP3 inflammasome in adipocytes when co-cultured with them. Additionally, the reduction of miR-500a-5p expression in macrophages by using a miR-500a-5p inhibitor ameliorated the pro-inflammatory properties of the exosomes, and co-culturing these exosomes with adipocytes resulted in decreased expression of NLRP3 inflammasome-associated proteins in adipocytes. In contrast, induction of miR-500a-5p expression led to the opposite results. Moreover, the dual-luciferase assay confirmed that miR-500a-5p directly targeted the 3' UTR of Nrf2 mRNA. Unlike miR-500a-5p, Nrf2 exhibited an anti-inflammatory response.
Conclusion:
The results indicate that ATM-derived exosomal miR-500a-5p promotes NLRP3 inflammasome activation and adipose tissue inflammation through down-regulation of Nrf2 in adipocytes.
Insights
Adipose tissue macrophages (ATMs) release exosomes containing miR-500a-5p, which promotes inflammation in type 2 diabetes (T2DM) by activating the NLRP3 inflammasome and down-regulating Nrf2 in adipocytes.
Area of Science:
- Endocrinology
- Immunology
- Molecular Biology
Background:
- Type 2 diabetes (T2DM) involves insulin resistance and chronic inflammation.
- Adipose tissue macrophages (ATMs) mediate inflammation and influence insulin sensitivity via exosomes.
- The role of ATM-derived exosomal microRNAs (miRNAs) in T2DM pathogenesis is underexplored.
Purpose of the Study:
- Investigate the role of ATM-derived exosomal miRNAs in adipose tissue inflammation in T2DM.
- Determine the specific mechanism by which these miRNAs contribute to T2DM pathogenesis.
Main Methods:
- Isolated ATMs from visceral adipose tissue of patients with or without diabetes.
- Performed high-throughput RNA sequencing to identify differentially expressed miRNAs in ATM-derived exosomes.
- Utilized RAW264.7 macrophages and 3T3-L1 preadipocytes as a model system.
- Quantified miR-500a-5p expression using qRT-PCR and verified direct targeting of Nrf2 mRNA via dual-luciferase assay.
Main Results:
- miR-500a-5p was enriched in exosomes from high-glucose-treated macrophages.
- Exosomes containing miR-500a-5p induced NLRP3 inflammasome activation in adipocytes.
- Inhibiting miR-500a-5p in macrophages reduced exosome-induced inflammation in adipocytes.
- miR-500a-5p directly targets the 3' UTR of Nrf2 mRNA, which has anti-inflammatory properties.
Conclusions:
- ATM-derived exosomal miR-500a-5p promotes adipose tissue inflammation in T2DM.
- This promotion occurs through NLRP3 inflammasome activation and Nrf2 down-regulation in adipocytes.
