2017年6月19日，世界著名期刊《The Journal of Allergy and Clinical Immunology》在线发表了复旦大学生物医学研究院周玉峰课题组和约翰霍普金斯大学医学院Peisong Gao教授合作的一篇研究论文，研究揭示了甘露糖受体调节过敏性炎症反应的新机制--通过miR-511-3p调节巨噬细胞极化。相关研究成果题为《甘露糖受体通过miR-511-3p调节巨噬细胞极化和过敏性炎症》 (Mannose Receptor Modulates Macrophage Polarization and Allergic Inflammation through miR-511-3p)。周玉峰研究员为第一作者，
甘露糖受体(Mannose receptor，MR)属于C型凝集素超家族成员，可通过胞外区识别和结合特定的糖类分子，在识别病原体、递呈抗原和保持内环境稳定中发挥作用。该研究发现甘露糖受体基因敲除可以影响巨噬细胞极化，表现为M1巨噬细胞极化增强，而M2巨噬细胞极化减弱，MR基因敲除鼠体内过敏反应增强。但甘露糖受体细胞内部分非常短，缺乏细胞内信号转导结构，一个缺乏信号转导功能的受体分子如何影响细胞极化，这非常难于解释。研究者对MR基因分析后发现，MR基因第五内含子含有micrornAs(miR-511-3p), 甘露糖受体与miR-511-3p协同表达，miR-511-3p可抑制M1极化， MR通过协同表达的miR-511-3p调节巨噬细胞极化而调节过敏性炎症。
Mannose Receptor Modulates Macrophage Polarization and Allergic Inflammation through miR-511-3p
BackgroundMannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glyco-allergens, including cockroach allergens.
ObjectiveDetermine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p.
MethodsWe examined the MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) andMrc1-/- 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.
ResultsMrc1-/- 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.
ConclusionThese studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.