MicroRNA 33 Regulates the Population of Peripheral Inflammatory Ly6Chigh Monocytes through Dual Pathways

Abstract

MicroRNA 33 (miR-33) targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum high-density lipoprotein (HDL)-cholesterol (HDL-C) and ameliorates atherosclerosis. Although we previously reported that miR-33 deficiency increased peripheral Ly6C^high monocytes on an ApoE-deficient background, the effect of miR-33 on the monocyte population has not been fully elucidated, especially in a wild-type (WT) background. We found that Ly6C^high monocytes in miR-33^-/- mice were decreased in peripheral blood and increased in bone marrow (BM). Expansion of myeloid progenitors and decreased apoptosis in Lin^- Sca1⁺ c-Kit⁺ (LSK) cells were observed in miR-33^-/- mice. A BM transplantation study and competitive repopulation assay revealed that hematopoietic miR-33 deficiency caused myeloid expansion and increased peripheral Ly6C^high monocytes and that nonhematopoietic miR-33 deficiency caused reduced peripheral Ly6C^high monocytes. Expression of high-mobility group AT-hook 2 (HMGA2) targeted by miR-33 increased in miR-33-deficient LSK cells, and its knockdown abolished the reduction of apoptosis. Transduction of human apolipoprotein A1 and ABCA1 in WT mouse liver increased HDL-C and reduced peripheral Ly6C^high monocytes. These data indicate that miR-33 deficiency affects distribution of inflammatory monocytes through dual pathways. One pathway involves the enhancement of Hmga2 expression in hematopoietic stem cells to increase Ly6C^high monocytes, and the other involves the elevation of HDL-C to decrease peripheral Ly6C^high monocytes.

Keywords: HDL-C; atherosclerosis; microRNA; monocytes; stem cells.