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Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation.

ABSTRACT: Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

SUBMITTER: Pan Y

PROVIDER: S-EPMC6355214 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation.

Pan Yong Y Hui Xiaoyan X Hoo Ruby Lai Chong RLC Ye Dewei D Chan Cyrus Yuk Cheung CYC Feng Tianshi T Wang Yu Y Lam Karen Siu Ling KSL Xu Aimin A

The Journal of clinical investigation 20190122 2

Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of d ...[more]

PMID: 30667374

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Project description:BackgroundMacrophages are the most abundant infiltrating immune-related stromal cells present in and around tumors, showing different phenotypes and functions. M2 macrophages mainly exert immunosuppressive functions and promote tumor growth. Exosomes are emerging as important mediators of cross-talk between tumor cells and the microenvironment. CircRNAs are novel members of non-coding RNAs that regulate cancer proliferation and progression. However, the mechanism by which exosomal circRNA regulates macrophage polarization in renal cell carcinoma (RCC) is still largely unknown.MethodsRCC-derived exosomes were characterized using transmission electron microscopy and nanoparticle tracking analysis (NTA). CCK-8, wound healing, and Transwell assays were performed to assess whether exosomes would affect the proliferation, migration, and invasion of RCC. Furthermore, we performed a bioinformatics analysis to identify circRNAs in RCC serum-derived exosomes from the GEO database. The fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circSAFB2. Bioinformatics analyses (StarBase 2.0) were used to pool the miRNA targets of circSAFB2. Luciferase assays were performed to verify the direct interactions. Western blotting was used to detect markers of macrophage M2 polarization. Lastly, mouse xenograft and bioluminescence imaging were used to examine the clinical relevance of exosomal circSAFB2 in vivo.ResultsWe report the circRNA derived from SAFB2 and evaluate its biological function in promoting the immune escape of RCC. We found that circSAFB2 was highly expressed in RCC tissues and RCC-derived exosomes. Furthermore, we demonstrated that exosomal circSAFB2 mediates the polarization of M2 macrophages through the miR-620/JAK1/STAT3 axis to promote RCC metastasis.ConclusionsOur data first demonstrated that circSAFB2 leads to immune escape from RCC by mediating M2 macrophage polarization via the miR-620/JAK1/STAT3 axis. These findings indicate a novel molecular mechanism of exosomal circSAFB2 in the progression of RCC and implicate circSAFB2 as a target for exosome-mediated tumor immune evasion.

Project description:BackgroundEmerging evidence has revealed that tumor-associated macrophages (TAMs) and exosomes play a crucial role in the microenvironment for tumor growth. However, the mechanisms through which exosomal miRNAs modulate TAMs and tumor development in breast cancer are not fully understood.MethodsWe constructed a macrophage model and an indirect coculture system consist of breast cancer cells and macrophages. Exosomes were isolated from BC cells culture supernatant and identified by transmission electron microscopy, Western blot and Nanosight LM10 system. The expression of miR-148b-3p in exosomes was determined by qRT-PCR and the effect of exosomal miR-148b-3p on macrophage polarization was measured using qRT-PCR and ELISA. The proliferation, migration and invasion of BC cells were estimated by EdU, wound healing assay and transwell assay. We employed bioinformatics, luciferase reporter assay and Western blot to identify the target gene of miR-148b-3p. Western blot was used to clarify the mechanism of exosomal miR-148b-3p mediated the crosstalk between BC cells and M2 macrophages.ResultsCancer-derived exosomes could induce M2 polarization of macrophages, which promoted the migration and invasion of breast cancer cells. We found that exosomal miR-148b-3p was overexpressed in breast cancer cell-derived exosomes and correlated with lymph node metastasis, late tumor stage and worse prognosis. Upregulated miR-148b-3p expression in exosomes modulated macrophage polarization by targeting TSC2, which promoted the proliferation and might affect migration and invasion of breast cancer cells. Interestingly, we found that exosomal miR-148b-3p could induce M2 macrophage polarization via the TSC2/mTORC1 signaling pathway in breast cancer.ConclusionOverall, our study elucidated that miR-148b-3p could be transported by exosomes from breast cancer cells to surrounding macrophages and induced M2 polarization by targeting TSC2, providing novel insights for breast cancer therapy.

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Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation.

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Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation.

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