Allergen exposure early in life is a strong predictor for the development of allergic asthma. Particularly, exposure to cockroach allergen can lead to allergic sensitization and increase the risk of developing allergic asthma. During the pilot stage for this proposal we have made a substantive breakthrough in understanding an important link within the cockroach antigen-sensitization-asthma pathway. We have demonstrated that the mannose receptor (MRC1/CD206) provides an impressive protective function in cockroach allergen induced airway inflammation. Our recent pilot study suggests that deletion of MRC1 in mice exacerbates cockroach allergen-induced lung inflammation, along with a tendency to polarize macrophages toward a M1 macrophage (inflammatory) phenotype. This finding was at first perplexing because MRC1 lacks a traditional signaling motif, therefore, the mechanisms underlying MRC1 mediated macrophage polarization and allergen induced lung inflammation remained obscure. Our breakthrough for a deeper understanding of this pathway came with the recognition of a key regulatory microRNA (miR-511-3p, the functional strand of miR-511). The miR-511-3p is encoded within the MRC1 gene and transcriptionally co-regulated in macrophages. This proposal centers on our novel hypothesis that the impressive protective effect of the mannose receptor on allergen-induced macrophage polarization and lung inflammation is due to the regulatory influences of miR-511-3p. Indeed, we have found that miR-511-3p was significantly lower in the blood of asthmatics compared to non-asthmatics, miR-511-3p is significantly increased in lung macrophages from cockroach extract-challenged mice, miR-511-3p is significantly reduced in bone marrow derived macrophages (BMDMs) lacking the MRC1, and BMDMs over-expressing miR-511-3p tend to polarize toward a M2 phenotype. These exciting data set the stage to critically evaluate the functional significance of miR-511-3p in MRC1-mediated macrophage polarization and allergen-induced allergic inflammation.
Aim 1 proposes studies to detect the levels of miR-511-3p in serum and monocyte-derived macrophages and analyze their associations with allergic asthma, particularly those with cockroach allergy.
Aim 2 proposes experiments to determine the role of miR-511-3p in MRC1-mediated macrophage polarization by over- or knockdown-expressing miR-511-3p in macrophages and in allergen-induced lung inflammation by generating bone-marrow chimeric mice with hematopoietic stem/progenitor cells (HS/PCs) miR-511-3p over- expression or knock-down and by using miR-511 mimic treatment.
Aim 3 proposes experiments to identify the potential targets for miR-511-3p by using miR-511-3p overexpression or inhibition experiments, luciferase reporter and biotin pulldown assays. Together, this work will provide a framework to understand miRNA targets, and will lead to subsequent studies to probe the mechanisms underlying the MRC1/miR-511-3p-modulated macrophage activation and allergic inflammation with a focus on these identified targets. The study may ultimately offer an opportunity for the discovery of novel therapeutic targets for allergic asthma.
Exposure to cockroach allergen can lead to allergic sensitization and increase the risk of developing allergic asthma. Deletion of mannose receptor (MRC1) in mice exacerbates cockroach allergen-induced lung inflammation, along with a tendency to polarize macrophages toward a M1 phenotype. miR-511-3p is encoded within the MRC1 gene and transcriptionally co-regulated in macrophages. Thus, we will evaluate the functional significance of miR-511-3p in MRC1-mediated macrophage polarization and allergen-induced lung inflammation, which may ultimately lead to the discovery of novel therapeutic targets for allergic asthma.
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