Visceral Adipose MicroRNA 223 Is Upregulated in Human and Murine Obesity and Modulates the Inflammatory Phenotype of Macrophages.
Obesity in humans and mice is typified by an activated macrophage phenotype in the visceral adipose tissue (VAT) leading to increased macrophage-mediated inflammation. microRNAs (miRNAs) play an important role in regulating inflammatory pathways in macrophages, and in this study we compared miRNA expression in the VAT of insulin resistant morbidly obese humans to a non-obese cohort with normal glucose tolerance. miR-223-3p was found to be significantly upregulated in the whole omental tissue RNA of 12 human subjects, as were 8 additional miRNAs. We then confirmed that miR-223 upregulation was specific to the stromal vascular cells of human VAT, and found that miR-223 levels were unchanged in adipocytes and circulating monocytes of the non-obese and obese. miR-223 ablation increased basal / unstimulated TLR4 and STAT3 expression and LPS-stimulated TLR4, STAT3, and NOS2 expression in primary macrophages. Conversely, miR-223 mimics decreased TLR4 expression in primary macrophage, at the same time it negatively regulated FBXW7 expression, a well described suppressor of Toll-like receptor 4 (TLR4) signaling. We concluded that the abundance of miR-223 in macrophages significantly modulates macrophage phenotype / activation state and response to stimuli via effects on the TLR4/FBXW7 axis.
Department of Medicine, Division of Cardiovascular Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, United States of America.|Dorothy Davis Heart and Lung Institute, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Jeffrey A
http://orcid.org/0000-0002-5665-8894
JA
Deiuliis
Department of Medicine, Division of Cardiovascular Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, United States of America.
Rafay
R
Syed
Dorothy Davis Heart and Lung Institute, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Dheeraj
D
Duggineni
Dorothy Davis Heart and Lung Institute, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Jessica
J
Rutsky
Department of Medicine, Division of Cardiovascular Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, United States of America.
Palanivel
P
Rengasamy
Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Jie
J
Zhang
Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Kun
K
Huang
Department of Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Bradley
B
Needleman
Department of Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Dean
D
Mikami
Department of Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Kyle
K
Perry
Department of Surgery, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Jeffrey
J
Hazey
Department of Medicine, Division of Cardiovascular Medicine, University of Maryland, Baltimore, Baltimore, MD 21201, United States of America.|Dorothy Davis Heart and Lung Institute, The Ohio State University College of Medicine, Columbus, OH 43210, United States of America.
Sanjay
S
Rajagopalan
D000328:Adult; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D015331:Cohort Studies; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D035683:MicroRNAs; D052247:Nitric Oxide Synthase Type II; D051197:Toll-Like Receptor 4; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse