Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p

摘要

[[abstract]]BACKGROUND: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glyco-allergens, including cockroach allergens. OBJECTIVE: Determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. METHODS: We examined the MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1-/- mice. Role of miR-511-3p in macrophage polarization and cockroach allergen-induced lung inflammation in mice transfected with Adeno-Associated Virus (AAV)-miR-511-3p (AAV-CMV-miR-511-3p-eGFP) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. RESULTS: Mrc1-/- lung macrophages showed significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1-/- mice had an exacerbated lung inflammation with increased levels of cockroach allergen-specific IgE and Th2/Th17 cytokines in a cockroach allergen-induced mouse model compared to WT mice. Macrophages from Mrc1-/- mice showed significantly reduced levels of miR-511-3 and a M1 phenotype whereas over-expression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV-miR-511-3p showed a significant reduction in cockroach allergen-induced inflammation. Profiling of macrophages with or without miR-511-3p over-expression identified 729 differentially expressed genes, wherein the levels of Ptgds and its product PGD2 were significantly down-regulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. The plasma levels of miR-511-3p were significantly lower in human asthmatics compared to non-asthmatic subjects. CONCLUSION: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.