Hematopoietic miR155 Deficiency Enhances Atherosclerosis and Decreases Plaque Stability in Hyperlipidemic Mice

Abstract

microRNA-155 (miR155) is a central regulator of immune responses that is induced by inflammatory mediators. Although miR155 is considered to be a pro-inflammatory microRNA, in vitro reports show anti-inflammatory effects in lipid-loaded cells. In this study we examined the role of miR155 in atherosclerosis in vivo using bone marrow transplantation from miR155 deficient or wildtype mice to hyperlipidemic mice. Hematopoietic deficiency of miR155 enhanced atherosclerotic plaque development and decreased plaque stability, as evidenced by increased myeloid inflammatory cell recruitment to the plaque. The increased inflammatory state was mirrored by a decrease in circulating CD4+CD25+FoxP3+ regulatory T cells, and an increase in granulocytes (CD11b+Ly6G+) in blood of miR155−/− transplanted mice. Moreover, we show for the first time a crucial role of miR155 in monocyte subset differentiation, since hematopoietic deficiency of miR155 increases the ‘inflammatory’ monocyte subset (CD11b+Ly6G−Ly6Chi) and reduces ‘resident’ monocytes (CD11b+Ly6G−Ly6Clow) in the circulation. Furthermore, cytokine production by resident peritoneal macrophages of miR155−/− transplanted hyperlipidemic mice was skewed towards a more pro-inflammatory state since anti-inflammatory IL-10 production was reduced.In conclusion, in this hyperlipidemic mouse model miR155 acts as an anti-inflammatory, atheroprotective microRNA. Additionally, besides a known role in lymphoid cell development, we show a crucial role of miR155 in myeloid lineage differentiation.

ALK5 and ALK1 Play Antagonistic Roles in Transforming Growth Factor β-Induced Podosome Formation in Aortic Endothelial Cells

“…Impairment of BMP9 signaling is not restricted to genetic disorders. miR-155 is dysregulated in many pathological states, including vascular diseases (33,34). Our studies show that expression of miR-155 promotes podosome rosette formation in BAE cells.…”

MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

“…These findings are in good correspondence with a recent publication of Du et al, 35 which showed a reduced Ly6C hi monocyte subset in the spleen of global miR-155-deficient mice on an APOE -/-background. However, Donners et al 36 recently found a different result with significantly less Ly6C hi monocytes in the blood lymphocyte profile of mice with an exclusive deficiency of miR-155 in the hematopoietic system. A possible explanation for this discrepancy is that Donners et al 36 obtained their results in a model of chronic hyperlipidemia and exclusive hematopoietic miR-155 deficiency, whereas our model of femoral artery ligation represents an acute inflammatory stimulus in globally miR-155-deficient animals.…”

Upregulation of miRNA-155 expression by OxLDL in dendritic cells involves JAK1/2 kinase and transcription factors YY1 and MYB

“…On the other hand, research from our laboratory suggests that miR-155 plays a protective role in the development and progression of AS (19). In a murine model of hyperlipidemia, miR-155 was found to act as an anti-inflammatory and protective factor against AS (20).…”