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Reduced Levels of microRNAs miR-124a and miR-150 Are Associated with Increased Proinflammatory Mediator Expression in Krüppel-like Factor 2 (KLF2)-deficient Macrophages*

Palanikumar Manoharan,Joshua E. Basford,R. Pilcher-Roberts,J. Neumann,D. Hui,J. Lingrel

Published 2014 in Journal of Biological Chemistry

ABSTRACT

Background: Inactivation of Krüppel-like factor 2 (KLF2) in myeloid cells induces activation of proinflammatory mediators. Results: Macrophage KLF2 deficiency increases chemokine expression and modulates microRNA levels. Conclusion: KLF2 suppresses expression of proinflammatory chemokines Ccl2 and Cxcl1 via modulation of miR-124a and miR-150 levels in myeloid cells. Significance: The anti-inflammatory properties of KLF2 include modification of microRNA expression in macrophages. Previous studies have shown that the myeloid-specific deficiency of the transcription factor Krüppel-like factor 2 (KLF2) accelerates atherosclerosis in hypercholesterolemic Ldlr−/− mice due to the enhanced adhesion of myeloid cells to activated endothelial cells in the vessel wall. This study revealed elevated basal inflammation with elevated plasma levels of Ccl2, Ccl4, Ccl5, and Ccl11 in the myeloid-specific KLF2 knock-out (myeKlf2−/−) mice. Peritoneal macrophages isolated from myeKlf2−/− mice showed increased mRNA levels of several inflammatory mediators, including Ccl2, Ccl5, Ccl7, Cox-2, Cxcl1, and IL-6. In contrast, the levels of two microRNAs, miR-124a and miR-150, were lower in Klf2−/− macrophages compared with Klf2+/+ macrophages. Additional studies showed a direct inverse relationship between miR-124a levels with Ccl2 expression, with anti-miR-124a increasing Ccl2 mRNA levels in Klf2+/+ macrophages, whereas the restoration of miR-124a levels in Klf2−/− macrophages significantly reduced Ccl2 mRNA expression. Likewise, the inverse relationship was observed between miR-150 levels and Cxcl1 expression in Klf2+/+ and Klf2−/− mice. Moreover, miR150 likely regulates the miR124a expression and thus augments expression of inflammatory mediators in myeKlf2−/− macrophages. This study documented that the transcription factor KLF2 modulates inflammatory chemokine production via regulation of microRNA expression levels in immune cells.

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