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Isolation, Characterization, and Purification of Macrophages from Tissues Affected by Obesity-related Inflammation
Published on: April 3, 2017
MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages
Kathryn Miranda1, Xiaoming Yang1, Marpe Bam1
1Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, 29209, USA.
Background/Objectives:
Obesity is a pandemic disorder that is characterized by accumulation of adipose tissue and chronic low-grade inflammation that is driven primarily by adipose tissue macrophages (ATMs). While ATM polarization from pro-(M1) to anti-(M2) inflammatory phenotype influences insulin sensitivity and energy expenditure, the mechanisms of such a switch are unclear. In the current study, we identified epigenetic pathways including microRNAs (miR) in ATMs that regulate obesity-induced inflammation.
Subjects/Methods:
Male C57BL/6J mice were fed normal chow diet (NCD) or high-fat diet (HFD) for 16 weeks to develop lean and diet-induced obese mice, respectively. Transcriptome microarrays, microRNA microarrays, and MeDIP-Seq were performed on ATMs isolated from visceral fat. Pathway analysis and bone marrow-derived macrophage (BMDM) transfections further allowed computational and functional analysis of miRNA-mediated ATM polarization.
Results:
ATMs from HFD-fed mice were skewed toward M1 inflammatory phenotype. Concurrently, the expression of miRs 30a-5p, 30c-5p, and 30e-5p was downregulated in ATMs from HFD mice when compared to mice fed NCD. The miR-30 family was shown to target Delta-like-4, a Notch1 ligand, whose expression was increased in HFD ATMs. Inhibition of miR-30 in conditioned BMDM triggered Notch1 signaling, pro-inflammatory cytokine production, and M1 macrophage polarization. In addition, DNA hypermethylation was observed in mir30-associated CpG islands, suggesting that HFD downregulates miR-30 through epigenetic modifications.
Conclusions:
HFD-induced obesity downregulates miR-30 by DNA methylation thereby inducing Notch1 signaling in ATMs and their polarization to M1 macrophages. These findings identify miR-30 as a regulator of pro-inflammatory ATM polarization and suggest that miR-30 manipulation could be a therapeutic target for obesity-induced inflammation.
Insights
Obesity-induced inflammation involves adipose tissue macrophages (ATMs) switching to a pro-inflammatory M1 state. This study reveals that microRNA-30 (miR-30) downregulation, via DNA methylation, drives this switch, offering a potential therapeutic target.
Area of Science:
- Immunology
- Metabolic Diseases
- Epigenetics
Background:
- Obesity is a global pandemic characterized by adipose tissue accumulation and chronic low-grade inflammation, primarily driven by adipose tissue macrophages (ATMs).
- The polarization of ATMs from an anti-inflammatory (M2) to a pro-inflammatory (M1) phenotype is crucial in obesity-induced inflammation, but the underlying mechanisms remain unclear.
- MicroRNAs (miRs) are implicated as regulators of cellular processes, including inflammation.
Purpose of the Study:
- To investigate the role of epigenetic pathways, specifically microRNAs (miRs) in ATMs, in regulating obesity-induced inflammation.
- To elucidate the mechanisms by which ATM polarization occurs in diet-induced obesity.
Main Methods:
- Male C57BL/6J mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 16 weeks.
- Transcriptome, microRNA microarrays, and MeDIP-Seq were performed on ATMs isolated from visceral fat.
- Computational and functional analyses, including bone marrow-derived macrophage (BMDM) transfections, were used to study miR-mediated ATM polarization.
Main Results:
- ATMs from HFD-fed mice exhibited a shift towards the M1 inflammatory phenotype.
- The expression of the miR-30 family (miR-30a-5p, miR-30c-5p, miR-30e-5p) was significantly downregulated in ATMs from HFD mice.
- The miR-30 family targets Delta-like-4 (DLL4), a Notch1 ligand. Inhibition of miR-30 in BMDMs promoted Notch1 signaling, pro-inflammatory cytokine production, and M1 polarization.
- DNA hypermethylation was observed in CpG islands associated with miR-30, indicating epigenetic downregulation by HFD.
Conclusions:
- High-fat diet-induced obesity downregulates miR-30 through DNA methylation, leading to the activation of Notch1 signaling and M1 polarization of ATMs.
- These findings identify the miR-30 family as a key regulator of pro-inflammatory ATM polarization in obesity.
- Manipulation of miR-30 presents a potential therapeutic strategy for combating obesity-induced inflammation.
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