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

Abstract

Allergic inflammation is accompanied by the coordinated expression of a myriad of genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) are a class of short single-stranded RNA molecules that posttranscriptionally silence gene expression and have been shown to fine-tune gene transcriptional networks because single miRNAs can target hundreds of genes. Considerable attention has been focused on the key role of miRNAs in regulating homeostatic immune architecture and acquired immunity. Recent studies have identified miRNA profiles in multiple allergic inflammatory diseases, including asthma, eosinophilic esophagitis, allergic rhinitis, and atopic dermatitis. Specific miRNAs have been found to have critical roles in regulating key pathogenic mechanisms in allergic inflammation, including polarization of adaptive immune responses and activation of T cells (eg, miR-21 and miR-146), regulation of eosinophil development (eg, miR-21 and miR-223), and modulation of IL-13-driven epithelial responses (eg, miR-375). This review discusses recent advances in our understanding of the expression and function of miRNAs in patients with allergic inflammation, their role as disease biomarkers, and perspectives for future investigation and clinical utility.

Figure 1. Schematic showing the regulation of the adaptive immune system by miR-21 in allergic inflammatory responses

Th1 and Th2 cells exist in a balanced state. Allergen or IL-13 upregulates miR-21 expression, which represses target gene IL-12 and in turn inhibits Th1 differentiation. Decreased production of the Th1 cytokine IFN-γ causes unopposed Th2 activation and increased production of Th2 cytokines. The Th2 cytokines may further amplify the miR-21-mediated responses. A highly conserved miR-21 seed sequence in the 3′UTR of IL-12p35 is shown in the insert at the top left corner; the seed sequence is shaded in gray.

Figure 2. Schematic showing miR-21 and miR-223 have opposite effect in eosinophil progenitor proliferation

Relative cell number of eosinophil progenitor cultures derived from wild-type (black line), miR-223^−/− (red line) & miR-21^−/− (purple line) mice is shown. Targeted ablation of miR-21 decreases eosinophil progenitor proliferation. Targeted ablation of miR-223 increases eosinophil progenitor proliferation.

Figure 3. Schematic showing the known roles of a commonly regulated set of miRNAs and their targets in allergic inflammation

The Th1 and Th2 cells exist in a balanced state and inhibit each other’s differentiation. MiR-21 inhibits IL-12 and in turn inhibits Th1 differentiation. MiR-146 promotes Treg-mediated suppression of Th1 cells, likely by targeting STAT-1. The suppression of Th1 response promotes a Th2-dominant response with Th2 cytokine IL-13 production. Let-7 inhibits IL-13 production, and downregulation of let-7 likely further amplifies the Th2 response. In T cells, miR-155 promotes both the Th1 and Th2 response by inhibiting the inhibitor CTLA-4. In macrophages, miR-155 attenuates IL-1-mediated responses by downregulating IL-13 receptor alpha 1 (IL-13Rα1). IL-13 inhibits miR-375 expression in epithelial cells, and miR-375 may both potentiate and inhibit IL-13-mediated responses in epithelial cells. IL-13 inhibits miR-133a in smooth muscle cells, and this increases the expression of the small GTPase RhoA that mediates smooth muscle contraction. The miRNAs and their direct targets are shown in red. DC, dendritic cell.