College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China.
National Translational Science Center for Molecular Medicine and Department of Cell Biology, Fourth Military Medical University, No. 169 Changle West Road, Xi'an 710032, China; Basic Medical Academy, Shaanxi University of Chinese Medicine, Xianyang 712046, China.
Int Immunopharmacol. 2021 Jul;96:107783. doi: 10.1016/j.intimp.2021.107783. Epub 2021 Jun 1.
MicroRNAs play a variety of roles in the progress of inflammation. Herein, we investigated the roles of miR-223 in governing macrophage polarization balance in the progress of sepsis. We firstly observed that miR-223 was down-regulated at the early phase and up-regulated at the late phase of sepsis in macrophages; the levels of miR-223 were positively correlated to the ratio of M2 macrophages during sepsis. In miR-223 knockout mice, we observed that miR-223 was dispensable for efficient pro-inflammatory responses, but was required for efficient M2-associated phenotype and function. miR-223 deletion increased clinical scores of sepsis, leading to increased mortality in septic mice. Furthermore, we found that miR-223 expression in M2-type macrophages was controlled by interleukin (IL)-4, but not IL-10; IL-4 antibodies were able to downregulate the levels of miR-223, increased the expression of targeted genes Nfat5 and Rasa1, reduced the ratio of M2 macrophages, resulting in a decreased survival rate in septic mice. Meanwhile, miR-223 deficient macrophages appeared a markedly decreased M2-type polarization when induced by IL-4, but did not affect macrophages skew to M2 phenotype induced by IL-10. Taken together, our results demonstrate that miR-223 acts as an important regulator to modulate IL-4-meditated M2-type polarization of macrophages via targeting to Nfat5 and Rasa1 to control the progress of sepsis.
MicroRNAs 在炎症的进展中发挥着多种作用。在这里，我们研究了 miR-223 在调控脓毒症中巨噬细胞极化平衡中的作用。我们首先观察到，miR-223 在巨噬细胞脓毒症的早期阶段下调，在晚期阶段上调；miR-223 的水平与脓毒症期间 M2 巨噬细胞的比例呈正相关。在 miR-223 敲除小鼠中，我们观察到 miR-223 对于有效的促炎反应是可有可无的，但对于有效的 M2 相关表型和功能是必需的。miR-223 的缺失增加了脓毒症的临床评分，导致脓毒症小鼠的死亡率增加。此外，我们发现 M2 型巨噬细胞中的 miR-223 表达受白细胞介素（IL）-4 调控，但不受 IL-10 调控；IL-4 抗体能够下调 miR-223 的水平，增加靶向基因 Nfat5 和 Rasa1 的表达，减少 M2 型巨噬细胞的比例，从而降低脓毒症小鼠的存活率。同时，当由 IL-4 诱导时，miR-223 缺陷型巨噬细胞的 M2 型极化明显减少，但不影响由 IL-10 诱导的巨噬细胞向 M2 表型的极化。总之，我们的研究结果表明，miR-223 通过靶向 Nfat5 和 Rasa1 作为一种重要的调节剂，调节 IL-4 介导的巨噬细胞 M2 型极化，从而控制脓毒症的进展。
