Delivery of miR-214 via extracellular vesicles downregulates Xbp1 expression and pro-inflammatory cytokine genes in macrophages.

Gonzalo Almanza, Stephen Searles, Maurizio Zanetti
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Abstract

Aim: Tumor-infiltrating macrophages are tumor-promoting and show activation of the unfolded protein response (UPR). The transcription factor X-box binding protein 1 (XBP1) is a conserved element of the UPR. Upon activation, the UPR mediates the transcriptional activation of pro-inflammatory cytokines and immune suppressive factors, hence contributing to immune dysregulation in the tumor microenvironment (TME). miR-214 is a short non-coding miRNA that targets the 3'-UTR of the Xbp1 transcript. Here, we tested a new method to efficiently deliver miR-214 to macrophages as a potential new therapeutic approach.

Methods: We generated miR-214-laden extracellular vesicles (iEV-214) in a murine B cell and demonstrated that iEV-214 were enriched in miR-214 between 1,500 - 2,000 fold relative to control iEVs.

Results: Bone marrow-derived macrophages (BMDM) treated with iEV-214 for 24 h underwent a specific enrichment in miR-214, suggesting transfer of the miR-214 payload from the iEVs to macrophages. iEV-214 treatment of BMDM markedly reduced (> 50%) Xbp1 transcription under endoplasmic reticulum stress conditions compared to controls. Immune-related genes downstream of XBP1s (Il-6, Il-23p19, and Arg1) were also reduced by 69%, 51%, and 34%, respectively.

Conclusions: Together, these data permit to conclude that iEV-214 are an efficient strategy to downregulate the expression of Xbp1 mRNA and downstream genes in macrophages. We propose miRNA-laden iEVs are a new approach to target macrophages and control immune dysregulation in the TME.

通过细胞外囊泡输送 miR-214 可下调巨噬细胞中 Xbp1 的表达和促炎细胞因子基因。
目的:肿瘤浸润巨噬细胞具有肿瘤促进作用,并显示出未折叠蛋白反应(UPR)的激活。转录因子 X-box 结合蛋白 1(XBP1)是 UPR 的一个保守要素。激活后,UPR 会介导促炎细胞因子和免疫抑制因子的转录激活,从而导致肿瘤微环境(TME)中的免疫失调。miR-214 是一种短的非编码 miRNA,以 Xbp1 转录本的 3'-UTR 为靶标。在此,我们测试了一种新方法,将 miR-214 有效递送至巨噬细胞,作为一种潜在的新治疗方法:方法:我们在小鼠 B 细胞中生成了富含 miR-214 的细胞外囊泡(iEV-214),并证明 iEV-214 中 miR-214 的含量比对照 iEV 高出 1,500 - 2,000 倍:用iEV-214处理骨髓衍生巨噬细胞(BMDM)24小时后,miR-214发生了特异性富集,表明miR-214有效载荷从iEVs转移到了巨噬细胞。XBP1s 下游的免疫相关基因(Il-6、Il-23p19 和 Arg1)也分别减少了 69%、51% 和 34%:综合这些数据,我们可以得出结论:iEV-214 是下调巨噬细胞中 Xbp1 mRNA 及下游基因表达的有效策略。我们认为,含有 miRNA 的 iEV 是靶向巨噬细胞和控制 TME 中免疫失调的一种新方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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