Regulation of Inflammatory Phenotype in Macrophages by a Diabetes-Induced Long Non-coding RNA

  1. Rama Natarajan1,*
  1. 1Department of Diabetes and Division of Molecular Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA.
  2. 2Current address: Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea.
  3. 3Departments of Computer and Information Science, Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway (P.S.).,
  4. 4Department of Pathology and Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX.
  1. *Corresponding authors: Rama Natarajan, Email: RNatarajan{at}coh.org, Marpadga A. Reddy, Email: mreddy{at}coh.org

Abstract

The mechanisms by which macrophages mediate the enhanced inflammation associated with diabetes complications are not completely understood. We used RNA-seq to profile the transcriptome of bone marrow macrophages isolated from diabetic db/db mice and identified 1648 differentially expressed genes compared to control db/+ mice. Data analyses revealed that diabetes promoted a pro-inflammatory, pro-fibrotic and dysfunctional alternatively activated macrophage phenotype possibly via transcription factors involved in macrophage function. Notably, diabetes altered levels of several long non-coding RNAs (lncRNAs). Because, the role of lncRNAs in diabetic complications is unknown, we further characterized the function of lncRNA E330013P06 which was up-regulated in macrophages from db/db and diet-induced insulin resistant type-2 diabetic mice, but not from type-1 diabetic mice. It was also up-regulated in monocytes from type-2 diabetes patients. E330013P06 was also increased along with inflammatory genes, in mouse macrophages treated with high glucose and palmitic acid. E330013P06 overexpression in macrophages induced inflammatory genes, enhanced responses to inflammatory signals, and increased foam cell formation. In contrast, siRNA-mediated E330013P06 gene silencing inhibited inflammatory genes induced by the diabetic stimuli. These results define the diabetic macrophage transcriptome, and novel functional roles for lncRNAs in macrophages that could lead to lncRNA based therapies for inflammatory diabetic complications.

  • Received February 25, 2014.
  • Accepted June 26, 2014.

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  1. Diabetes
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