Department of Emergency, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.
Department of Emergency, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
J Biol Chem. 2024 Jun;300(6):107334. doi: 10.1016/j.jbc.2024.107334. Epub 2024 May 3.
The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) is a critical regulator of glycolysis and plays a key role in modulating the inflammatory response, thereby contributing to the development of inflammatory diseases such as sepsis. Despite its importance, the development of strategies to target PFKFB3 in the context of sepsis remains challenging. In this study, we employed a miRNA-based approach to decrease PFKFB3 expression. Through multiple meta-analyses, we observed a downregulation of miR-106a-5p expression and an upregulation of PFKFB3 expression in clinical sepsis samples. These changes were also confirmed in blood monocytes from patients with early sepsis and from a mouse model of lipopolysaccharide (LPS)-induced sepsis. Overexpression of miR-106a-5p significantly decreased the LPS-induced increase in glycolytic capacity, inflammatory response, and pyroptosis in macrophages. Mechanistically, we identified PFKFB3 as a direct target protein of miR-106a-5p and demonstrated its essential role in LPS-induced pyroptosis and inflammatory response in macrophages. Furthermore, treatment with agomir-miR-106a-5p conferred a protective effect in an LPS mouse model of sepsis, but this effect was attenuated in myeloid-specific Pfkfb3 KO mice. These findings indicate that miR-106a-5p inhibits macrophage pyroptosis and inflammatory response in sepsis by regulating PFKFB3-mediated glucose metabolism, representing a potential therapeutic option for the treatment of sepsis.
6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶同工酶 3（PFKFB3）是糖酵解的关键调节因子，在调节炎症反应中发挥着关键作用，从而有助于炎症性疾病（如败血症）的发展。尽管它很重要，但在败血症的背景下针对 PFKFB3 开发策略仍然具有挑战性。在这项研究中，我们采用了基于 microRNA 的方法来降低 PFKFB3 的表达。通过多次荟萃分析，我们观察到临床败血症样本中 miR-106a-5p 的表达下调和 PFKFB3 的表达上调。这些变化也在早期败血症患者的血液单核细胞和脂多糖（LPS）诱导的败血症小鼠模型中得到了证实。miR-106a-5p 的过表达显著降低了 LPS 诱导的巨噬细胞糖酵解能力、炎症反应和细胞焦亡的增加。在机制上，我们确定 PFKFB3 是 miR-106a-5p 的直接靶蛋白，并证明了其在 LPS 诱导的巨噬细胞细胞焦亡和炎症反应中的重要作用。此外，用 agomir-miR-106a-5p 治疗 LPS 诱导的败血症小鼠模型具有保护作用，但在髓样细胞特异性 Pfkfb3 KO 小鼠中，这种作用减弱。这些发现表明，miR-106a-5p 通过调节 PFKFB3 介导的葡萄糖代谢来抑制败血症中巨噬细胞的细胞焦亡和炎症反应，代表了治疗败血症的一种潜在治疗选择。
