MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers

Abstract

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.

Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases

“…41 These findings are not just of academic interest as miR-21 is upregulated in multiple human Th2-associated diseases including eosinophilic esophagitis, atopic dermatitis, and ulcerative colitis. [42][43][44] In addition, miR-21 has been reported to be upregulated in human airway epithelial cells in response to IL-13 treatment and suppresses TLR-2 signaling in an animal model of asthma. 45 AntagomiRs or anti-miRs are a class of chemically engineered nucleotides that silences miRNA expression in vitro and/or in vivo.…”

“…Analysis of esophageal eosinophil level and a myriad of esophageal transcripts for correlation with miR-21 demonstrated impressive correlations of miR-21 with esophageal eosinophil count, cell-specific markers for eosinophils, and CCL-26 (eotaxin-3), which is functionally involved in eosinophil recruitment. 44,73 Both miR-146a and miR-146b have been found to be upregulated in patients with eosinophilic esophagitis. 44 A previous report by Lu et al found that miR-146a could selectively suppress Th1 responses.…”

“…44,73 Both miR-146a and miR-146b have been found to be upregulated in patients with eosinophilic esophagitis. 44 A previous report by Lu et al found that miR-146a could selectively suppress Th1 responses. 74 Utilizing miR-146a-deficient mice, the authors showed that miR-146a deficiency selectively impaired Treg-mediated suppression of Th1 responses, leaving the suppression of Th2 and Th17 responses intact.…”

“…Using plasma samples from patients with eosinophilic esophagitis, three of the differentially regulated miRNAs in the esophageal biopsies, miR-146a, miR-146b, and miR-223, were also found to be differentially regulated in the plasma. 44 Since circulating miRNAs often exist in exosomes, which can be taken up by other cells, 22,25,75,76 28,29 An esophageal biopsy needs to be obtained every time a diagnosis is made and on subsequent follow-ups to assess therapeutic response. The circulating plasma miRNAs, including miR-146a and miR-223, could potentially serve as non-invasive biomarkers for diagnosis or assessment of therapeutic response alone or in combination with other biomarkers.…”

“…77 One of the most downregulated miRNA in eosinophilic esophagitis is miR-375. 44 Notably, miR-375 is downregulated after IL-13 stimulation in both human bronchial and human esophageal epithelial cells. 78 In addition, miR-375 has been reported to be downregulated in Th2-associated diseases including atopic dermatitis and ulcerative colitis.…”