Abstract
Immunological diseases, including asthma, autoimmunity and immunodeficiencies, affect a growing percentage of the population with significant unmet medical needs. As we slowly untangle and better appreciate these complex genetic and environment-influenced diseases, new therapeutically targetable pathways are emerging. Non-coding RNA species, which regulate epigenetic, transcriptional and translational responses are critical regulators of immune cell development, differentiation and effector function, and may represent one such new class of therapeutic targets. In this review we focus on type-2 immune responses, orchestrated by TH2 cell-derived cytokines, IL-4, IL-5 and IL-13, which stimulate a variety of immune and tissue responses- commonly referred to as type-2 immunity. Evolved to protect us from parasitic helminths, type-2 immune responses are observed in individuals with allergic diseases, including Asthma, atopic dermatitis and food allergy. A growing number of studies have identified the involvement of various RNA species, including microRNAs (miRNA) and long non-coding (lncRNA), in type-2 immune responses and in both clinical and pre-clinical disease settings. We highlight these recent findings, identify gaps in our understanding and provide a perspective on how our current understanding can be harnessed for novel treat opportunities to treat type-2 immune-mediated diseases.
Highlights
Because of the limited number of studies directly related to long non-coding RNAs (lncRNAs) in type-2 inflammation, the remainder of this section will focus on broad concepts central to lncRNA biology, which may be applied to cell types and molecular processes related to type-2 inflammation
We discovered that miR-146a is necessary for the commitment of T cells to a TH 2 polarization program, as miR-146a-/T cells led to a mixed response in HDM-challenged lungs, and were unable to mount a competent TH 2 response to expel the intestinal helminth, Trichuris muris, a parasite that requires the full engagement of the type-2 immune response [109]
These miRNA s are worth discussing as some investigators have discovered a strong link between them and the establishment of an adaptive type-2 immune response in murine models, as they target many of the essential nodes of Th2 cell differentiation and effector function, like Gata3 and il4 genes
Summary
Evolved and constantly adapting to the changing environment, the immune system is tightly regulated in mammals, protecting us from a barrage of both infectious and non-infectious insults. For TH 2 cell differentiation, IL-4 receptor ligation provides the 3rd necessary extracellular cue, in addition to TCR engagement and co-stimulation, to initiate a transcriptional re-organization required for TH 2 cell identity Both dendritic cells and basophils have emerged as important IL-4-secreting and antigen-presenting innate cells required for optimal TH 2 cell differentiation [14,15,16,17,18,19,20,21,22,23]. Following TH 2 differentiation, chromatin remodeling at conserved non-coding sequence-1 (CNS-1), DNase I hypersensitivity (DHS) site, CNS-2, and the conserved intron 1 sequence of IL-4 (CIRE) in the il locus facilitates rapid cytokine transcription [55,56,57] Poised in such a state, it may only require a low level of T cell activation to induce translation and secretion of type-2 cytokines
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