MicroRNA-155: microtuning the allergic concert
Authors: F. Cortinas‐Elizondo, S. von Gunten
Journal: Allergy (2015)

MicroRNAs (miRNAs) are small noncoding single-stranded RNAs that play a critical role in the regulation of gene expression by repressing the translation and inducing degradation of miRNAs. Given their diversity and their efficacy as post-transcriptional regulators, miRNA expression has wide-ranging implications on cellular functions. Dysregulation of this modulatory system can compromise immune homeostasis, leading to medical conditions, including allergic disease. Several studies have identified altered miRNA expression profiles in asthma, allergic rhinitis, eosinophil esophagitis, and atopic dermatitis 1-4. For example, it has been recently shown in Allergy that miR-19a is highly expressed in samples of patients with severe asthma and enhances the proliferation of bronchial epithelial cells by targeting the TGFβR2 gene 4. Another miRNA, miR-23b, has been shown to promote tolerogenic activity of OVA-stimulated dendritic cells (DCs) by inhibiting Notch1 and NF-kB signaling pathways 5. In the current issue of Allergy, Zech et al. 6 provide evidence that miR-155 is essential in DCs for the initiation and maintenance of allergic airway inflammation. Using a DC-driven murine model, it was demonstrated that miR-155 deficiency in DCs resulted in a marked decrease in common features of allergic airway inflammation, that is, airway eosinophilia, production of Th2-cytokines, peribronchial inflammation, and a reduced bronchial hyper-responsiveness. miR-155 expression was upregulated in OVA- and HDM-pulsed DCs, and its deficiency resulted in an impaired maturation of DCs. Consequently, when coculturing OVA-primed miR-155−/− DCs with OVA-specific naive T cells, they failed to orchestrate a full Th2 response, as seen by a reduction in IL-4, IL-5, and IL-13 cytokine production. Previously, functional and mechanistic studies have been performed to elucidate the role of miR-155 in allergic airway inflammation. For example, it has been reported that miR-155 is required for a proper function of B and T lymphocytes and DCs, as indicated by attenuated immune responses in miR-155-deficient mice, characterized by impaired antibody secretion, T-cell proliferation, and cytokine production 7. Moreover, it was shown that miR-155 is essential in regulating CD4+ T-cell activation by targeting c-Maf, a potent transactivator of the IL-4 promoter, resulting in attenuated Th2 cell responses in vivo 7. Furthermore, recent data showed that miR-155 is able to modulate allergen-induced Th2 responses in the lung by targeting the transcription factors PU.1 2 and S1pr1 8. Additionally, it has been demonstrated that miR-155 plays a pivotal role in FCεRI-mediated activation of mast cells by regulating components of the PI3Kγ signaling pathway 9. In this issue, Zech et al. provide further insights on the molecular mechanisms of miR-155 activity in allergic airway inflammation, by showing a novel cross talk of miR-155 and ATP-type 2 purinergic receptors (P2R) signaling in DCs (Fig. 1) 6. It has been previously reported that extracellular ATP, released into the airways, contributes to the initiation and maintenance of allergic airway inflammation via signaling through P2R on DCs 10. For instance, ATP-P2RY2 signaling promotes recruitment of DCs and eosinophils into the lung 11, whereas ATP-P2RX7 mediates IL-1β maturation and release 12. Now, Zech et al. 6 performed an in silico prediction of miR-155 targets and identified potential binding sites of miR-155 on Entpd1 and Entpd3, members of the ectonucleotidase family responsible for ATP degradation. In accordance, Entpd1 and Entpd3 expression levels were upregulated in lung tissue and DCs of miR-155−/− mice, which presented an increased local ATPase activity compared to wild-type animals. In concordance, the increased ectonucleotidase activity of miR-155−/− mice affected their ATP-induced P2RY2 and P2RX7 signaling in DCs, resulting in their disturbed migration and reduction in IL-1β secretion. We have recently highlighted the potential of pleiotropic immunomodulatory molecules, such as glucocorticoids, vitamin D, or intravenous immunoglobulin (IVIG), that target diverse cellular players or pathways involved in the complex pathogenesis of allergic inflammation 13. Likewise, miRNA-based therapeutic strategies seem promising in view of the accumulating evidence pointing toward a role of specific miRNAs in the modulation of multiple molecular processes associated with the pathogenesis or maintenance of atopic diseases. Yet, further mechanistic studies, such as the one by Zech et al. in this issue of Allergy, are required to fully explore the repertoire of relevant miRNAs and to dissect the specific disease-associated pathways and networks that are modulated by these molecules. The authors declare no conflict of interest.