Shang Yan, Sun Yahong, Xu Jing, Ge Xiahui, Hu Zhenli, Xiao Jiang, Ning Yunye, Dong Yuchao, Bai Chong
Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China.
Department of Respiratory Medicine, Haining People's Hospital of Zhejiang Province, Zhejiang 314400, China.
Mol Ther Nucleic Acids. 2020 Mar 6;19:951-960. doi: 10.1016/j.omtn.2019.10.049. Epub 2020 Jan 9.
Asthma is the most common chronic disease and is characterized by airway remodeling and chronic inflammation. Increasingly, studies have found that the activation and M1 phenotypic transformation of macrophages play important roles in asthma progress, including airway remodeling. However, the reversal of M1 macrophages to the M2 phenotype has been shown to attenuate airway remodeling. Exosomes are nano-sized extracellular vesicles derived from endosomes; they play direct roles in governing physiological and pathological conditions by the intracellular transfer of bioactive cargo, such as proteins, enzymes, nucleic acids (microRNA [miRNA], mRNA, DNA), and metabolites. However, transfer mechanisms are unclear. To uncover potential therapeutic mechanisms, we constructed an ovalbumin-induced asthma mouse model and lipopolysaccharide-induced RAW264.7 macrophages cells. High-throughput sequencing showed that mmu_circ_0001359 was downregulated in asthmatic mice when compared with normal mice. Adipose-derived stem cell (ADSC)-exosome treatment suppressed inflammatory cytokine expression by the conversion of M1 macrophages to the M2 phenotype, under lipopolysaccharide-induced conditions. Exosomes from mmu_circ_0001359 overexpression in ADSCs increased therapeutic effects, in terms of cytokine expression, when compared with wild-type exosomes. Luciferase reporter assays confirmed that exosomes from mmu_circ_0001359-modified ADSCs attenuated airway remodeling by enhancing FoxO1 signaling-mediated M2-like macrophage activation, via sponging miR-183-5p. In conclusion, mmu_circ_0001359-enriched exosomes attenuated airway remodeling by promoting M2-like macrophages.
哮喘是最常见的慢性疾病，其特征为气道重塑和慢性炎症。越来越多的研究发现，巨噬细胞的激活和M1表型转化在哮喘进展（包括气道重塑）中起重要作用。然而，已表明M1巨噬细胞向M2表型的逆转可减轻气道重塑。外泌体是源自内体的纳米级细胞外囊泡；它们通过生物活性物质（如蛋白质、酶、核酸（微小RNA [miRNA]、信使核糖核酸 [mRNA]、脱氧核糖核酸 [DNA]）和代谢物）的细胞内转移，在调控生理和病理状况中发挥直接作用。然而，其转移机制尚不清楚。为揭示潜在的治疗机制，我们构建了卵清蛋白诱导的哮喘小鼠模型和脂多糖诱导的RAW264.7巨噬细胞。高通量测序显示，与正常小鼠相比，哮喘小鼠体内的mmu_circ_0001359表达下调。在脂多糖诱导的条件下，脂肪来源干细胞（ADSC）外泌体处理通过将M1巨噬细胞转化为M2表型来抑制炎性细胞因子表达。与野生型外泌体相比，ADSCs中mmu_circ_0001359过表达的外泌体在细胞因子表达方面增强了治疗效果。荧光素酶报告基因检测证实，mmu_circ_0001359修饰的ADSCs来源的外泌体通过海绵化miR-183-5p增强FoxO1信号介导的M2样巨噬细胞激活，从而减轻气道重塑。总之，富含mmu_circ_0001359的外泌体通过促进M2样巨噬细胞减轻气道重塑。
