State Key Laboratory of Reproductive Medicine and Offspring Health, National Vaccine Innovation Platform of Nanjing Medical University, Jiangsu Key Laboratory of Pathogen Biology, Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
Shock. 2024 Apr 1;61(4):611-619. doi: 10.1097/SHK.0000000000002236. Epub 2023 Oct 2.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Macrophages play important roles in the inflammatory process of sepsis by secreting chemokines. Chemokine (CC-motif) ligand 2 (CCL-2) is one of the main proinflammatory chemokines secreted by macrophages that plays a critical role in the recruitment of more monocytes and macrophages to the sites of injury in sepsis, but the mechanisms that regulate CCL-2 expression in macrophages during sepsis are still unknown. In the present study, by using the LPS-induced endotoxemia model, we found that LPS induced the expression of microRNA (miR)-155 and CCL-2 in endotoxemic mice and RAW264.7 cells. MiR-155 mimics or miR-155 inhibitor treatment experiment suggested that miR-155 was sufficient to increase LPS-induced CCL-2 expression in macrophages, but miR-155 was not the only factor promoting CCL-2 expression. We further demonstrated that miR-155-induced increase of CCL-2 promoted chemotaxis of additional macrophages, which subsequently enhanced lung injury in endotoxemic mice. Serum/glucocorticoid regulated kinase family member 3 (SGK3), a potential target of miR-155, was identified by RNA sequencing and predicted by TargetScan and miRDB. We further confirmed miR-155 regulated SGK3 to increase LPS-induced CCL-2 by using miR-155 mimics and SGK3 overexpression. Thus, our study demonstrates that miR-155 targets SGK3 to increase LPS-induced CCL-2 expression in macrophages, which promotes macrophage chemotaxis and enhances organs injury during endotoxemia. Our study contributed to a better understanding of the mechanisms underlying the inflammatory response during sepsis.
脓毒症是一种危及生命的器官功能障碍，是由宿主对感染的失调反应引起的。巨噬细胞通过分泌趋化因子在脓毒症的炎症过程中发挥重要作用。趋化因子（CC 基序）配体 2（CCL-2）是巨噬细胞分泌的主要促炎趋化因子之一，在脓毒症中损伤部位募集更多单核细胞和巨噬细胞中发挥关键作用，但调节巨噬细胞中 CCL-2 表达的机制在脓毒症中仍不清楚。在本研究中，通过使用 LPS 诱导的内毒素血症模型，我们发现 LPS 诱导内毒素血症小鼠和 RAW264.7 细胞中 miR-155 和 CCL-2 的表达。miR-155 模拟物或 miR-155 抑制剂处理实验表明，miR-155 足以增加巨噬细胞中 LPS 诱导的 CCL-2 表达，但 miR-155 不是促进 CCL-2 表达的唯一因素。我们进一步证明，miR-155 诱导的 CCL-2 增加促进了额外巨噬细胞的趋化，随后增强了内毒素血症小鼠的肺损伤。血清/糖皮质激素调节激酶家族成员 3（SGK3），miR-155 的一个潜在靶标，通过 RNA 测序和 TargetScan 和 miRDB 预测。我们进一步证实，miR-155 通过 miR-155 模拟物和 SGK3 过表达调节 SGK3 增加 LPS 诱导的 CCL-2。因此，我们的研究表明，miR-155 靶向 SGK3 增加 LPS 诱导的巨噬细胞中 CCL-2 的表达，促进巨噬细胞趋化并增强内毒素血症期间器官损伤。我们的研究有助于更好地理解脓毒症炎症反应的机制。
