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

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 1; pp. 350 - 364.e8
• Main Authors: Zhou, Yufeng, Do, Danh C., Ishmael, Faoud T., Squadrito, Mario Leonardo, Tang, Ho Man, Tang, Ho Lam, Hsu, Man-Hsun, Qiu, Lipeng, Li, Changjun, Zhang, Yongqing, Becker, Kevin G., Wan, Mei, Huang, Shau-Ku, Gao, Peisong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2018; Elsevier Limited
• Subjects: Allergens - immunology; Allergies; Allergy and Immunology; Animals; Antigens; Asthma; Asthma - etiology; Asthma - metabolism; Asthma - pathology; Bone marrow; Cockroaches - immunology; Cytokines; Flow cytometry; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Genetic Vectors - genetics; Green fluorescent protein; Helper cells; Hypersensitivity; Hypersensitivity - etiology; Hypersensitivity - metabolism; Hypersensitivity - pathology; Immunoglobulin E; Inflammation; Inner city; Laboratories; Lectins, C-Type - metabolism; Lungs; Lymphocytes T; macrophage; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Mannose; Mannose Receptor; Mannose-Binding Lectins - metabolism; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; Microscopy; miR-511-3p; Models, Biological; Plasma levels; Pneumonia - etiology; Pneumonia - metabolism; Pneumonia - pathology; Polarization; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Immunologic; RNA Interference; Rodents; PAS; M-CSF; ROCK2; CLR; LV; BM; LTBP1; GFP; FITC; FDR; MRC1; Mannose receptor; miRNA; qPCR; PTGDS; WT; SSC; miR-511-3p; AF; H&E; macrophage; asthma; BAL; CMV; AAV; CRE; TLR4; DC; CEBPA; Cockroach extract; Auto-fluorescence; C-type lectin-like domains; Bronchoalveolar lavage; CCAAT/Enhancer Binding Protein Alpha; MiR-511-3p; C-type lectin receptor; Rho Associated Coiled-Coil Containing Protein Kinase 2; Prostaglandin D2 Synthase; False Discovery Rate; Adeno-associated virus; Toll-like receptor 4; Mannose receptor (MRC1/CD206); Lentivirus; CTLD; microRNA; Latent Transforming Growth Factor Beta Binding Protein 1; Macrophage
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.04.049

Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens. We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1−/− mice. The 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–cytomegalovirus–miR-511-3p–enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. Mrc1−/− lung macrophages showed a 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 with WT mice. Macrophages from Mrc1−/− mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression 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 overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D2 synthase (Ptgds) and its product PGD2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511-3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects. These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation. [Display omitted]