Department of Microbiology and Immunology, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Medical Laboratory Center, Northwest Women's and Children's Hospital Affiliated to Xi'an Jiaotong University, Xi'an, China.
Int Immunopharmacol. 2021 Dec;101(Pt B):108347. doi: 10.1016/j.intimp.2021.108347. Epub 2021 Nov 16.
LncRNA-Cox2 has been reported to regulate macrophage polarization, and the activation of macrophages is a major participant in the pathogenesis of sepsis. Therefore, we explored whether lncRNA-Cox2 was involved in the progression of sepsis. In this study, we established a cecal ligation and puncture (CLP) mouse model and found that silencing lncRNA-Cox2 in CLP mice improved the 7-day survival rate, and alleviated the increase of blood bacterial burdens, systemic inflammatory response, and pulmonary dysfunction induced by CLP. Besides, interference with lncRNA-Cox2 declined the percentage of M1 macrophages and increased the percentage of M2 macrophages in the spleens of CLP mice. In vitro, the knockdown of lncRNA-Cox2 suppressed LPS-induced inflammation and M1 macrophage marker expression, and promoted M2 macrophage marker expression in primary peritoneal macrophages and RAW264.7 cells. Moreover, lncRNA-Cox2 induced CREB phosphorylation by binding to CREB, and increased phosphorylated-CREB enrichment in the C/EBPβ promoter region, so as to promote C/EBPβ transcription, thereby activating the CREB-C/EBPβ cascade. In addition, overexpressing lncRNA-Cox2 enhanced the effect of LPS on inflammation and macrophage polarization, which was reversed by treatment with 666-15 (an inhibitor of CREB). In conclusion, silencing lncRNA-Cox2 restrained the progression of sepsis in mice by modulating macrophage polarization and inflammatory response through suppressing CREB-C/EBPβ pathway.
LncRNA-Cox2 已被报道可调节巨噬细胞极化，而巨噬细胞的激活是脓毒症发病机制的主要参与者。因此，我们探讨了 lncRNA-Cox2 是否参与了脓毒症的进展。在这项研究中，我们建立了盲肠结扎穿刺（CLP）小鼠模型，发现沉默 CLP 小鼠中的 lncRNA-Cox2 提高了 7 天生存率，并减轻了 CLP 引起的血细菌负荷增加、全身炎症反应和肺功能障碍。此外，干扰 lncRNA-Cox2 降低了 CLP 小鼠脾脏中 M1 巨噬细胞的比例，并增加了 M2 巨噬细胞的比例。在体外，lncRNA-Cox2 的敲低抑制了 LPS 诱导的炎症和 M1 巨噬细胞标志物的表达，并促进了原代腹腔巨噬细胞和 RAW264.7 细胞中 M2 巨噬细胞标志物的表达。此外，lncRNA-Cox2 通过与 CREB 结合诱导 CREB 磷酸化，并增加磷酸化-CREB 在 C/EBPβ 启动子区域的富集，从而促进 C/EBPβ 转录，从而激活 CREB-C/EBPβ 级联反应。此外，过表达 lncRNA-Cox2 增强了 LPS 对炎症和巨噬细胞极化的作用，用 666-15（CREB 的抑制剂）处理可逆转这一作用。总之，沉默 lncRNA-Cox2 通过抑制 CREB-C/EBPβ 通路来调节巨噬细胞极化和炎症反应，从而抑制脓毒症在小鼠中的进展。
