Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou 510220, PR China; Department of Pharmacology, Shantou University Medical College, Shantou 515041, PR China.
Department of Pharmacology, Shantou University Medical College, Shantou 515041, PR China.
Int Immunopharmacol. 2023 Sep;122:110415. doi: 10.1016/j.intimp.2023.110415. Epub 2023 Jul 2.
Monocyte-derived exosomes (Exos) have been implicated in inflammation-related autoimmune/inflammatory diseases via transferring bioactive cargoes to recipient cells. The purpose of this study was to investigate the possible effect of monocyte-derived Exos on the initiation and the development of acute lung injury (ALI) by delivering long non-coding RNA XIST. Key factors and regulatory mechanisms in ALI were predicted by bioinformatics methods. BALB/c mice were treated with lipopolysaccharide (LPS) to establish an ALI in vivo model and then injected with Exos isolated from monocytes transduced with sh-XIST to evaluate the effect of monocyte-derived exosomal XIST on ALI. HBE1 cells were co-cultured with Exos isolated from monocytes transduced with sh-XIST for further exploration of its effect. Luciferase reporter, RIP and RNA pull-down assays were performed to verify the interaction between miR-448-5p and XIST, miR-448-5p and HMGB2. miR-448-5p was significantly poorly expressed while XIST and HMGB2 were highly expressed in the LPS-induced mouse model of ALI. Monocyte-derived Exos transferred XIST into HBE1 cells where XIST competitively inhibited miR-448-5p and reduced the binding of miR-448-5p to HMGB2, thus upregulating the expression of HMGB2. Furthermore, in vivo data revealed that XIST delivered by monocyte-derived Exos downregulated miR-448-5p expression and up-regulated HMGB2 expression, ultimately contributing to ALI in mice. Overall, our results indicate that XIST delivered by monocyte-derived Exos aggravates ALI via regulating the miR-448-5p/HMGB2 signaling axis.
单核细胞衍生的外泌体（Exos）通过将生物活性货物转移到受体细胞中，参与与炎症相关的自身免疫/炎症性疾病。本研究旨在通过递送长链非编码 RNA XIST 来研究单核细胞衍生的 Exos 对急性肺损伤（ALI）的发生和发展的可能影响。通过生物信息学方法预测 ALI 中的关键因素和调节机制。用脂多糖（LPS）处理 BALB/c 小鼠以建立体内 ALI 模型，然后用转染 sh-XIST 的单核细胞分离的 Exos 注射，以评估单核细胞衍生的外泌体 XIST 对 ALI 的影响。将 HBE1 细胞与转染 sh-XIST 的单核细胞分离的 Exos 共培养，以进一步探索其对 ALI 的影响。荧光素酶报告、RIP 和 RNA 下拉实验验证了 miR-448-5p 与 XIST、miR-448-5p 与 HMGB2 之间的相互作用。在 LPS 诱导的 ALI 小鼠模型中，miR-448-5p 表达显著下调，而 XIST 和 HMGB2 表达显著上调。单核细胞衍生的 Exos 将 XIST 转染到 HBE1 细胞中，其中 XIST 竞争性抑制 miR-448-5p 并减少 miR-448-5p 与 HMGB2 的结合，从而上调 HMGB2 的表达。此外，体内数据显示，单核细胞衍生的 Exos 递送来的 XIST 下调了 miR-448-5p 的表达并上调了 HMGB2 的表达，最终导致小鼠的 ALI。总之，我们的研究结果表明，单核细胞衍生的 Exos 递送来的 XIST 通过调节 miR-448-5p/HMGB2 信号轴加重 ALI。
