Effect of ApoE deficiency on microRNA expression in bone marrow derived macrophages (BMDM)

ApoE exerts pleiotropic properties in controlling inflammation and myeloid cell activation. We here uncover microRNA regulation as yet another mechanism that ApoE acts upon to control immune cell activity and inflammatory response. We compared the expression of microRNAs in BMDM derived from ApoE-KO (EKO) or WIldtype (WT) mice and identified 78 microRNAs to be differentially expressed between these two groups. Among these microRNAs, we identified miR-146a-5p to be highly upregulated in WT BMDM as compared to EKO BMDM. This is consistent with our prior study that reports a role of ApoE in promoting the biogenesis of this microRNA via the transcription of its host gene PU.1 (Spi1) in monocytes/macrophages. Of note, miR-146a-5p is recognized as a potent inhibitor of the NF-?B signaling pathway via the inactivation of IRAK1 and TRAF6. Furthermore, we identified mIR-142a-3p as downregulated in WT BMDM as compared to EKO BMDM. This microRNA has been reported to control important metabolic functions in myeloid cells by targeting the long chain fatty acid transporter CPT1A, thereby inhibiting fatty acid oxidation. Our data thus uncovers another novel of ApoE in controlling lipid metabolism in myeloid cells by suppressing the expression of miR-142a-3p. Taken together, our data provide a novel framework for the microRNA signatures regulated by ApoE in myeloid cells. Moreover, we uncovered an important mechanism of which ApoE can regulate myeloid cell immunometabolism via the regulation of miR-146a-5p and miR-142a-3p. Overall design: To investigate the differential expression of microRNAs in ApoE-KO (EKO) BMDM versus Wildtype (WT) BMDM. Bone marrow cells are taken from age-matched male mice that are 6- to 12-week-old and cultured into BMDM. We then collected the total RNA and performed microRNA expression profiling analysis using data obtained from small RNA-seq of the two different cell groups. Three biological replicates (n = 3) were used for each group.