Dataset Information

MiR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.

ABSTRACT: The Notch pathway plays critical roles in the differentiation and polarized activation of macrophages; however, the downstream molecular mechanisms underlying Notch activity in macrophages remain elusive. Our previous study has identified a group of microRNAs that mediate Notch signaling to regulate macrophage activation and tumor-associated macrophages (TAMs). In this study, we demonstrated that miR-148a-3p functions as a novel downstream molecule of Notch signaling to promote the differentiation of monocytes into macrophages in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF). Meanwhile, miR-148a-3p promoted M1 and inhibited M2 polarization of macrophages upon Notch activation. Macrophages overexpressing miR-148a-3p exhibited enhanced ability to engulf and kill bacteria, which was mediated by excessive production of reactive oxygen species (ROS). Further studies using reporter assay and Western blotting identified Pten as a direct target gene of miR-148a-3p in macrophages. Macrophages overexpressing miR-148a-3p increased their ROS production through the PTEN/AKT pathway, likely to defend against bacterial invasion. Moreover, miR-148a-3p also enhanced M1 macrophage polarization and pro-inflammatory responses through PTEN/AKT-mediated upregulation of NF-?B signaling. In summary, our data establish a novel molecular mechanism by which Notch signaling promotes monocyte differentiation and M1 macrophage activation through miR-148a-3p, and suggest that miR-148a-3p-modified monocytes or macrophages are potential new tools for the treatment of inflammation-related diseases.

SUBMITTER: Huang F

PROVIDER: S-EPMC5650608 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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miR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.

Huang Fei F Zhao Jun-Long JL Wang Liang L Gao Chun-Chen CC Liang Shi-Qian SQ An Dong-Jie DJ Bai Jian J Chen Yan Y Han Hua H Qin Hong-Yan HY

Frontiers in immunology 20171016

The Notch pathway plays critical roles in the differentiation and polarized activation of macrophages; however, the downstream molecular mechanisms underlying Notch activity in macrophages remain elusive. Our previous study has identified a group of microRNAs that mediate Notch signaling to regulate macrophage activation and tumor-associated macrophages (TAMs). In this study, we demonstrated that miR-148a-3p functions as a novel downstream molecule of Notch signaling to promote the differentiati ...[more]

PMID: 29085372

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Project description:Long noncoding RNAs (LncRNAs) have been implicated in the regulation of adipocyte and osteoblast differentiation. However, the functional contributions of LncRNAs to adipocyte or osteoblast differentiation remain largely unexplored. In the current study we have identified a novel LncRNA named peroxisome proliferator-activated receptor γ coactivator-1β-OT1 (PGC1β-OT1). The expression levels of PGC1β-OT1 were altered during adipogenic and osteogenic differentiation from progenitor cells. 5'- and 3'-rapid amplification of cDNA ends (RACE) revealed that PGC1β-OT1 is 1759 nt in full length. Overexpression of PGC1β-OT1 in progenitor cells inhibited adipogenic differentiation, whereas silencing of endogenous PGC1β-OT1 induced adipogenic differentiation. By contrast, overexpression of PGC1β-OT1 in progenitor cells stimulated, whereas silencing of PGC1β-OT1 inhibited osteogenic differentiation. In vivo experiment showed that silencing of endogenous PGC1β-OT1 in marrow stimulated fat accumulation and decreased osteoblast differentiation in mice. Mechanism investigations revealed that PGC1β-OT1 contains a functional miR-148a-3p binding site. Overexpression of the mutant PGC1β-OT1 with mutation at the binding site failed to regulate either adipogenic or osteogenic differentiation. In vivo crosslinking combined with affinity purification studies demonstrated that PGC1β-OT1 physically associated with miR-148a-3p through the functional miR-148a-3p binding site. Furthermore, PGC1β-OT1 affected the expression of endogenous miR-148a-3p and its target gene lysine-specific demethylase 6b (KDM6B). Supplementation of miR-148a-3p in progenitor cells blocked the inhibitory effect of PGC1β-OT1 on adipocyte formation. Moreover, overexpression of Kdm6b restored the osteoblast differentiation which was inhibited by silencing of endogenous PGC1β-OT. Our studies provide evidences that the novel LncRNA PGC1β-OT1 reciprocally regulates adipogenic and osteogenic differentiation through antagonizing miR-148a-3p and enhancing KDM6B effect.

Project description:The immunologic interaction between parenchyma cells and encircling inflammatory cells is thought to be the most important mechanism of biliary damage and repair in primary sclerosing cholangitis (PSC). Monocytes/macrophages as master regulators of hepatic inflammation have been demonstrated to contribute to PSC pathogenesis. Macrophages coordinate with liver regeneration, and multiple phenotypes have been identified with diverse expressions of surface proteins and cytokine productions. We analyzed the expression of Notch ligand Jagged1 in polarized macrophages and investigated the relevance of Notch signalling activation in liver regeneration. M1 or M2 macrophages were generated from mouse bone marrow-derived macrophages (BMDMs) by classical or alternative activation, respectively. Then, the expression levels of Jagged1 (Jag1) of each phenotype were measured. The effects of polarized BMDMs on the expression of hepatic progenitor cell- (HPC-) specific markers and hairy and enhancer of split-1 (HES1) in HPCs in coculture were also analyzed. Monocyte-macrophage and Notch signalling-associated gene signatures were evaluated in the GEO database (access ID: GSE61260) by gene set enrichment analysis (GSEA). M1 macrophages were found associated with elevated Jag1 expression, which increased the fraction of HPC with self-renewing phenotypes (CD326+CD44+ or CD324+CD44+) and HES1 expression level in cocultured HPC. Blocking Jagged1 by siRNA or antibody in the coculture system attenuates HPC self-renewing phenotypes as well as HES1 expression in HPC. GSEA data show that macrophage activation and Notch signalling-associated gene signatures are enriched in PSC patients. These findings suggest that M1 macrophages promote an HPC self-renewing phenotype which is associated with Notch signalling activation within HPC. In the liver of PSC patients, the prevalence of activated macrophages, with M1 polarized accounting for the main part, is associated with increment of Notch signalling and enhancement of HPC self-renewal.

Dataset Information

MiR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.

Publications

miR-148a-3p Mediates Notch Signaling to Promote the Differentiation and M1 Activation of Macrophages.

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