Depletion of miR-21 in dendritic cells aggravates renal ischemia-reperfusion injury
Depletion of miR-21 in dendritic cells aggravates renal ischemia-reperfusion injury
复制标题
树突状细胞中miR-21的耗竭会加重肾缺血再灌注损伤
DOI：
10.1096/fj.201903222rr
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发表时间：
2020-07-15
期刊：
影响因子：
4.8
通讯作者：
Ding, Xiaoqiang
中科院分区：
文献类型：
--
作者：
Jia, Ping;Pan, Tianyi;Ding, Xiaoqiang
树突状细胞（Dendritic cells，DC）在肾缺血再灌注损伤（IRI）的病理生理过程中起重要作用。DCs表型调节的机制及其功能尚未完全清楚。在这项研究中，我们研究了miR-21在体外和体内对DC表型调节的作用，并进一步研究了miR-21过表达DC或miR-21缺陷DC对肾IRI的影响。我们发现缺氧/复氧（H/R）处理抑制了骨髓来源的树突状细胞（BMDCs）中miR-21的表达，并显著增加了成熟DC（CD 11 c（+）/MHC-II+/CD 80（+））的百分比。使用选择的microRNA模拟物，我们成功地诱导了BMDC中miR-21的上调，这诱导了未成熟DC表型和抗炎DC反应。然而，miR-21在BMDCs中的缺失促进了DC在H/R下的成熟。连续转移miR-21过表达的BMDCs可以减轻肾脏IR诱导的促炎细胞因子产生和急性肾损伤（阿基）。与野生型小鼠相比，在经历肾IR的DC中具有miR-21缺陷的小鼠显示出更严重的肾功能障碍和炎症反应。此外，成熟DC的表面标志物趋化因子C受体7（CCR 7）是miR-21的靶基因，BMDC中CCR 7的沉默导致H/R下成熟DC减少。总之，我们的研究结果强调了miR-21作为DCs亚群表型的关键调节因子和肾IRI的潜在治疗靶点。
Dendritic cells (DCs) play an important role in the pathophysiology of renal ischemia-reperfusion injury (IRI). The mechanisms underlying DCs phenotypic modulation and their function are not fully understood. In this study, we examined the effect of miR-21 on the phenotypic modulation of DCs in vitro and in vivo, and further investigated the impact of miR-21-overexpression DC or miR-21-deficient DC on renal IRI. We found that treatment with hypoxia/reoxygenation (H/R) suppressed miR-21 expression in bone marrow-derived dendritic cells (BMDCs), and significantly increased the percentage of mature DCs (CD11c(+)/MHC-II+/CD80(+)). Using a selection of microRNA mimics, we successfully induced the upregulation of miR-21 in BMDCs, which induced immature DC phenotype and an anti-inflammatory DC response. However, deletion of miR-21 in BMDCs promoted maturation of DCs under H/R. Adoptive transfer of miR-21-overexpression BMDCs could alleviate renal IR-induced pro-inflammatory cytokines production and acute kidney injury (AKI). Mice with miR-21 deficiency in DCs subjected to renal IR showed more severe renal dysfunction and inflammatory response compared with wild-type mice. In addition, chemokine C receptor 7 (CCR7), a surface marker of mature DC, was a target gene of miR-21, and silencing of CCR7 in BMDCs led to reduced mature DCs under H/R. In conclusion, our findings highlight miR-21 as a key regulator of DCs subset phenotype and a potential therapeutic target in renal IRI.