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MiR-21 is one of the most up-regulated miRNAs in multiple allergic diseases associated with eosinophilia and has been shown to positively correlate with eosinophil levels. Herein, we show that miR-21 is up-regulated during IL-5-driven eosinophil differentiation from progenitor cells in vitro. Targeted ablation of miR-21 leads to reduced eosinophil progenitor cell growth. Furthermore, miR-21−/− eosinophil progenitor cells have increased apoptosis as indicated by increased levels of annexin V positivity compared to miR-21+/+ eosinophil progenitor cells. Indeed, miR-21−/− mice have reduced blood eosinophil levels in vivo and reduced eosinophil colony forming unit capacity in the bone marrow. Using gene expression microarray analysis, we identified dysregulation of genes involved in cell proliferation (e,g, Ms4a3, Grb7), cell cycle and immune response as the most significant pathways affected by miR-21 in eosinophil progenitors. These results demonstrate that miR-21 can regulate the development of eosinophils by influencing eosinophil progenitor cell growth. Our findings have identified one of the first miRNAs with a role in regulating eosinophil development. [ABSTRACT FROM AUTHOR]

Background: The role of microRNAs (miRNAs), a key class of regulators of mRNA expression and translation, in patients with eosinophilic esophagitis (EoE) has not been explored. Objective: We aimed to identify miRNAs dysregulated in patients with EoE and assess the potential of these miRNAs as disease biomarkers. Methods: Esophageal miRNA expression was profiled in patients with active EoE and those with glucocorticoid-induced disease remission. Expression profiles were compared with those of healthy control subjects and patients with chronic (noneosinophilic) esophagitis. Expression levels of the top differentially expressed miRNAs from the plasma of patients with active EoE and patients with EoE remission were compared with those of healthy control subjects. Results: EoE was associated with 32 differentially regulated miRNAs and was distinguished from noneosinophilic forms of esophagitis. The expression levels of the most upregulated miRNAs (miR-21 and miR-223) and the most downregulated miRNA (miR-375) strongly correlated with esophageal eosinophil levels. Bioinformatic analysis predicted interplay of miR-21 and miR-223 with key roles in the polarization of adaptive immunity and regulation of eosinophilia, and indeed, these miRNAs correlated with key elements of the EoE transcriptome. The differentially expressed miRNAs were largely reversible in patients who responded to glucocorticoid treatment. EoE remission induced a single miRNA (miR-675) likely to be involved in DNA methylation. Plasma analysis of the most upregulated esophageal miRNAs identified miR-146a, miR-146b, and miR-223 as the most differentially expressed miRNAs in the plasma. Conclusions: We have identified a marked dysregulated expression of a select group of miRNAs in patients with EoE and defined their reversibility with glucocorticoid treatment and their potential value as invasive and noninvasive biomarkers. [Copyright &y& Elsevier]

Recently, microRNAs have been shown to be involved in hematopoietic cell development, but their role in eosinophilopoiesis has not yet been described. In this article, we show that miR-223 is upregulated during eosinophil differentiation in an ex vivo bone marrow-derived eosinophil culture system. Targeted ablation of miR-223 leads to an increased proliferation of eosinophil pro-genitors. We found upregulation of a miR-223 target gene, IGF1R, in the eosinophil progenitor cultures derived from miR-223-/- mice compared with miR-223+/+ littermate controls. The increased proliferation of miR-223 eosinophil progenitors was reversed by treatment with an IGF1R inhibitor (picropodophyllin). Whole-genome microarray analysis of differentially regulated genes between miR-223+/+ and miR-223-/- eosinophil progenitor cultures identified a specific enrichment in genes that regulate hema-tologic cell development. Indeed, miR-223-/- eosinophil progenitors had a delay in differentiation. Our results demonstrate that microRNAs regulate the development of eosinophils by influencing eosinophil progenitor growth and differentiation and identify a contributory role for miR-223 in this process. [ABSTRACT FROM AUTHOR]