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

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.

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2

“…In particular, Mrc1-deficient mice showed significant reduction in CRE uptake, but unexpectedly, these mice have an exacerbation of CRE-induced airway inflammation. Although the underlying mechanisms remain uncertain, our studies suggest that Mrc1 deficiency in macrophages may lead to the alterations in allergen uptake and balance between classically activated (or M1) and alternatively activated (or M2) macrophage phenotypes (10) that may contribute to the exacerbation of airway inflammation.…”

“…C-type lectin receptors (CLRs) are pattern-recognition receptors that recognize allergenic glycans present on allergens, facilitating the endocytosis and presentation of pathogens that are critical in shaping the development of allergic asthma (1)(2)(3)(4)(5)(6)(7)(8). Most importantly, macrophage mannose receptor (MRC1/CD206), one of the major CLRs, has been shown to play an important role in mediating allergic sensitization (9,10), lung inflammation (10), and activation of innate immune cells (4,11). Our previous studies identified a critical role of MRC1 in allergen clearance as a natural defense mechanism and in limiting the progression and severity of allergic inflammation induced by cockroach allergen (cockroach extract, CRE) in a mouse model of asthma (10).…”

“…Most importantly, macrophage mannose receptor (MRC1/CD206), one of the major CLRs, has been shown to play an important role in mediating allergic sensitization (9,10), lung inflammation (10), and activation of innate immune cells (4,11). Our previous studies identified a critical role of MRC1 in allergen clearance as a natural defense mechanism and in limiting the progression and severity of allergic inflammation induced by cockroach allergen (cockroach extract, CRE) in a mouse model of asthma (10). In particular, Mrc1-deficient mice showed significant reduction in CRE uptake, but unexpectedly, these mice have an exacerbation of CRE-induced airway inflammation.…”

“…tion by affecting the translation and stability of their targeted mRNAs (12). miRs can target genes that orchestrate T helper 2 responses (13,14), phagocyte activation (10,15), and shape macrophage polarization and plasticity (16,17), all of which are important immunological processes in the pathogenesis of diseases (18). miR-511-3p is transcriptionally coregulated with the MRC1 gene in macrophages (10,19).…”

“…miRs can target genes that orchestrate T helper 2 responses (13,14), phagocyte activation (10,15), and shape macrophage polarization and plasticity (16,17), all of which are important immunological processes in the pathogenesis of diseases (18). miR-511-3p is transcriptionally coregulated with the MRC1 gene in macrophages (10,19). Recent studies have suggested that miR-511-3p controls the activation of tumor-associated macrophages (19), regulates intestinal inflammation by targeting Toll-like receptor 4 (TLR4) (20), and affects dendritic cell (DC) function by cross-talk with CLRs (21).…”