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MicroRNA-125a-5p overexpression in human macrophages

ABSTRACT: Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood arthropathy with features of autoinflammation. Monocytes and macrophages in SJIA have a complex phenotype with both pro- and anti-inflammatory properties that combine features of several well characterized in vitro conditions used to activate macrophages. An important anti-inflammatory phenotype is expression of CD163, a scavenger receptor that sequesters toxic pro-inflammatory complexes that is highly expressed in both active SJIA and macrophage activation syndrome (MAS). CD163 is most strongly upregulated by IL-10 (M(IL-10)), and not by other conditions that reflect features seen in SJIA monocytes such as M(LPS+IC). MicroRNA play key roles balancing and integrating cellular signals such as those in macrophage polarization, and as such we hypothesize microRNA regulate macrophage functional responses in SJIA including CD163 expression in vitro. We find that two microRNA previously found to be elevated in active SJIA, miR-125a-5p and miR-181c, significantly reduced macrophage CD163 expression through two distinct mechanisms. Neither microRNA was elevated in M(IL-10) with robust CD163 expression, but were instead induced in M(LPS+IC) where they restricted CD163 mRNA expression. Mir-181 species directly targeted CD163 mRNA for degradation. In contrast, transcriptome analysis of miR-125a-5p overexpression identified “cytokine-cytokine receptor interactions” as the most significantly repressed gene pathway, including decreased IL10RA, which is required for IL-10-mediated CD163 expression. Finally, overexpression of miR-181c inhibited CD163 anti-inflammatory responses to hemoglobin or high mobility group box 1 complexes. Together, these data show that microRNA utilize multiple mechanisms to integrate well characterized polarization phenotypes and regulate macrophage functional properties seen in SJIA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104853 | GEO | 2018/04/12

REPOSITORIES: GEO

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Project description:Somatic and germline mutations in GATA2 were recently identified in patients diagnosed with monoMAC, the hallmarks of which include monocytopenia, B-cell and NK-cell lymphopenia, susceptibility to opportunistic infections (e.g. MAC), and a strong propensity to develop hypocellular MDS/AML or CMML. GATA2 mutations are thought to result in loss of function or haploinsufficiency, but the precise mechanism for the development of cytopenias, immunodeficiency, and susceptibility to MDS remains to be elucidated. MicroRNA (miR) represents a unique mechanism of post-transcriptional gene regulation. In this study we generated microRNA profiles of patient derived monoMAC cell lines followed by functional studies to identify aberrant miRs and their targets, which could potentially cooperate with GATA2 deficiency in generating cytopenias and hematologic disease. In our study, eight miRs were significantly differentially expressed (≥ 2-fold; p ≤ 0.05) as determined by microRNA microarray profiles; miR-9, miR-181a-2-3p, miR-181c, miR-181c-3p, miR-486-3p, and miR-582-5p showed increased expression in monoMAC cell lines compared to controls, while miR-223 and miR-424-3p showed significantly decreased expression. Among the differentially expressed miRs that were validated by quantitative RT-PCR was miR-181c, which demonstrated a 2.2 fold increase in expression in monoMAC cell lines (p = 0.013). Among the target transcripts potentially regulated by miR-181c, MCL1 expression was significantly decreased (2 fold; p = 0.018) in monoMAC cell lines in comparison to control cell lines. Transient transfection of miR-181c in Ly8 cells resulted in 40% decrease of MCL1 mRNA level, suggesting that miR-181c negatively regulates MCL1 in MonoMAC. These findings indicate that monoMAC/GATA2 deficiency is associated with significantly decreased expression of MCL1 possibly through negative regulation involving miR-181c. Deletion of Mcl1 is known to cause apoptosis, loss of HSCs, and cytopenias in murine studies. Thus, down-regulation of MCL1 seen in monoMAC/GATA2 deficiency may similarly favor unregulated apoptosis and the depletion of hematopoietic progenitors resulting in cytopenias, immunodeficiency, and risk of MDS/AML.

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MicroRNA-125a-5p overexpression in human macrophages

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