Functional role of miR-511-3p in allergic asthma and its underlying mechanisms

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ABSTRACT Exposure to cockroach allergen can lead to allergic sensitization and an increased risk of allergic asthma. However, the underlying molecular mechanisms are currently not well-established. Our long-term goals are to elucidate the fundamental underlying mechanisms and identify novel therapeutic targets for allergic asthma. During the pilot studies, our group has made significant contributions to unraveling an important link between cockroach antigen and development of allergic asthma. Specifically, our profiling of N-linked glycans from cockroach allergen identified several major glycans with high affinity to mannose receptor, MRC1/CD206. Furthermore, we have identified a critical but previously unrecognized role of MRC1 in allergen clearance as a natural defense mechanism and in limiting the progression and severity of cockroach allergen-induced allergic inflammation in a mouse model of asthma. This occurs through alterations in macrophage clearance of the inhaled cockroach allergens and balance of M1/M2 macrophage polarization. This was at first perplexing because MRC1 lacks any known signaling motif, therefore, the signaling cascades of MRC1 in allergen-induced airway inflammation and macrophage polarization remain obscure. Our breakthrough for a deeper understanding of the MRC1 signaling pathway came with the recognition that a key regulatory miR-511-3p, encoded by both mouse and human MRC1 gene, is transcriptionally co-regulated with MRC1 in macrophages. These exciting findings lead us to propose a novel hypothesis that MRC1 is largely involved in allergen clearance as a natural defense mechanism, and MRC1-encoded miR-511-3p is involved in mediating MRC1 downstream immune responses and protecting against allergen-induced airway inflammation. This hypothesis is further buttressed by our recent findings that plasma levels of miR-511-3p were much lower in asthmatics compared to controls, and that adeno-associated virus (AAV)-mediated miR-511-3p over-expression ameliorated the allergen-induced airway inflammation in Mrc1-/- mice, but miR-511-3p knockout mice showed increased allergen-induced airway inflammation. These exciting data set the stage to critically evaluate the functional significance of miR-511-3p in allergic asthma and its underlying mechanisms. Three independent yet related specific aims are proposed. Aim 1 will determine the significance of miR-511-3p in allergic asthma by quantifying miR-511-3 in plasma, sputum and extracellular vesicles (EVs) from plasma and sputum of allergic asthmatics and testing its role in macrophage polarization and function. Aim 2 will define whether miR-511-3p protects against asthma using miR-511-3p global and macrophage conditional knockout mice (e.g., LysM-cre; miR-511-3pflox/flox) and mannose-decorated EV-miR- 511-3p-treated mice. Aim 3 will identify miR-511-3p targets by integrating gene profiling and our unique affinity- based transcriptomic approach for miR-511-3p binding partner mRNAs/long non-coding RNAs. Collectively, our studies will provide a conceptual framework linking allergens, MRC1, and miR-511-3p to key features of asthma. Ultimately, these studies may allow for the development of new diagnostic and therapeutic targets for asthma.