Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10-Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells
Antisense Oligonucleotide Treatment Enhances the Recovery of Acute Lung Injury through IL-10-Secreting M2-like Macrophage-Induced Expansion of CD4+ Regulatory T Cells
复制标题
反义寡核苷酸治疗通过分泌 IL-10 的 M2 样巨噬细胞诱导 CD4 调节性 T 细胞扩增增强急性肺损伤的恢复
DOI：
10.4049/jimmunol.1203233
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发表时间：
2013-04-15
影响因子：
4.4
通讯作者：
Xu, Lin
中科院分区：
文献类型：
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作者：
Guo, Zhongliang;Wen, Zhenke;Xu, Lin
microRNAs（miRNAs）已被证明是急性肺损伤（ALI）病理过程中的重要调节因子。然而，基于miRNA的治疗研究在ALI中的潜在作用仍然知之甚少。我们使用小鼠ALI模型评估了针对miR-155的反义寡核苷酸（ASO）对ALI发展的影响。我们发现miR-155阿索治疗可以促进ALI的恢复，如通过加速体重恢复、降低支气管肺泡灌洗（BAL）蛋白和促炎细胞因子水平以及减少BAL细胞数量所证明的。RAG 1（-/-）小鼠的连续细胞转移实验表明，CD 4（+）CD 25（+）调节性T细胞（TCRs）介导了ALI的恢复。机制证据显示，TcB在体内的增强扩增（主要由分泌IL-10的M2样巨噬细胞诱导）对于它们在miR-155 ASO治疗的ALI小鼠中的比例升高至关重要。最后，我们报道了miR-155的靶分子C/EBP β上调，并与巨噬细胞的IL-10分泌和M2样表型相关。这些数据为基于miRNA的治疗ALI提供了一个以前未知的机制，这最终可能有助于理解ALI的恢复和开发针对临床炎症性肺病的新治疗策略。免疫学杂志，2013，190：4337-4348。
MicroRNAs (miRNAs) have been shown as an important regulator in the pathologies of acute lung injury (ALI). However, the potential effect of miRNA-based therapeutic studies in ALI remains poorly understood. We assessed the effect of antisense oligonucleotides (ASOs) against miR-155 on the development of ALI using a murine ALI model. We found that miR-155 ASO treatment could enhance the recovery of ALI as evidenced by accelerated body weight back, reduced level of bronchoalveolar lavage (BAL) protein and proinflammatory cytokines, and reduced number of BAL cells. Adoptive cell transfer assay in RAG1(-/-) mice showed that CD4(+)CD25(+) regulatory T cells (Tregs) mediated the enhanced recovery of ALI. Mechanistic evidence showed that enhanced expansion of Tregs in vivo, dominantly induced by IL-10-secreting M2-like macrophages, was critical for their elevated proportion in miR-155 ASO-treated ALI mice. Finally, we report that C/EBP beta, a target molecule of miR-155, was upregulated and associated with IL-10 secretion and M2-like phenotype of macrophages. These data provided a previously unknown mechanism for miRNA-based therapy against ALI, which could ultimately aid the understanding of recovery of ALI and the development of new therapeutic strategies against clinical inflammatory lung disease. The Journal of Immunology, 2013, 190: 4337-4348.