Atopic dermatitis (AD), also called eczema, is characterized by allergic skin inflammation with remodeling and accumulation of immune cells, including T cells and mast cells (MC), but its pathogenesis remains poorly understood. Recalcitrant itching is most common and associated with poor quality of life for AD patients. Rising world-wide prevalence has been reported among children and adults, affecting at least 15% and 2-10% of each population, respectively. The high burden of disability related to eczema remains unfortunately consistent. In many AD cases, insufficient eczema relief and lack of clinical efficacy of current topical treatments, associated with deleterious side effects of immunosuppressive drugs have triggered many ongoing treatment studies, emphasizing the unmet medical need for better pharmacological options in AD. Because of its inflammatory components requiring the coordinated actions of diverse molecular pathways, we reasoned that microRNAs, small non coding RNAs recently recognized as potent epigenetic regulators of disease processes through mRNA targeting, could exert important functions in the spatiotemporal control of gene and protein expression observed during the development of AD. Little is known pertaining to such epigenetic changes occurring in AD. In addition, even though 80% of AD patients display high levels of circulating immunoglobulin (Ig) E, the Ig isotype detected in allergic patients, the allergic component of AD remains controversial. Located around blood vessels, skin-resident MC are key effectors of allergic reactions, increased in number in AD skin lesions of humans and mice. We have discovered that crosslinking of MC expressed high affinity receptors for IgE (Fc?RI) by allergen triggers MC activation, subsequent release of chemokines linked to Stat3 transcription factor and activation of sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate (S1P), a potent inflammatory and chemotactic lipid mediator. Using a well-established AD-like mouse model, we have identified a set of three miRNAs consistently downregulated in inflamed skins which leads to the up-regulation of many target genes involved in MC biology and immune cell recruitment. The objectives of this application are: to establish the miRNA profiling at the onset of AD and its association with MC functions; to elucidate the signaling pathways controlled by the miRNA triad and their relevance to S1P and chemokine production and MC activation. We anticipate our proposed studies will provide evidence for the importance of epigenetics in the regulation of AD initiation involving MC and S1P contributions to inflammatory cell recruitment through Stat3-mediated chemokine production, hence leading to AD progression. We are proposing these mechanistic insights will identify new molecular targets to prevent AD.
Atopic dermatitis, or eczema, is characterized by allergic skin inflammation with accumulation of immune cells, including mast cells primary responders in allergic disorders, but its pathogenesis remains poorly understood. We propose that epigenetic regulation of atopic dermatitis by microRNAs, small non coding molecules recently shown to regulate many biological processes, is critical to the initiation of cell infiltration through its regulation of local chemokine and S1P production in mast cells. We anticipate this innovative concept will pave the way for molecular target-based preventive rather than curative strategies of AD.
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