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

J Allergy Clin Immunol. 2018 Jan;141(1):350-364.e8. doi: 10.1016/j.jaci.2017.04.049. Epub 2017 Jun 17.

Abstract

Background: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens.

Objective: We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p.

Methods: 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.

Results: 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.

Conclusion: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.

Keywords: Mannose receptor; asthma; macrophage; miR-511-3p.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Animals
  • Asthma / etiology
  • Asthma / metabolism
  • Asthma / pathology
  • Cockroaches / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genetic Vectors / genetics
  • Hypersensitivity / etiology*
  • Hypersensitivity / metabolism*
  • Hypersensitivity / pathology
  • Lectins, C-Type / metabolism*
  • Macrophage Activation / genetics*
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Mannose Receptor
  • Mannose-Binding Lectins / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • Models, Biological
  • Pneumonia / etiology
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • RNA Interference
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Immunologic

Substances

  • Allergens
  • Lectins, C-Type
  • MRC1 protein, mouse
  • Mannose Receptor
  • Mannose-Binding Lectins
  • Membrane Glycoproteins
  • MicroRNAs
  • Mirn511 microRNA, mouse
  • Receptors, Cell Surface
  • Receptors, Immunologic