Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130 Dongdeok-Ro, Jung-Gu, Daegu, 41944, Republic of Korea.
Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, Republic of Korea.
Inflamm Res. 2023 Nov;72(10-11):1981-1997. doi: 10.1007/s00011-023-01796-y. Epub 2023 Sep 28.
Classically activated M1 macrophages, characterized by aberrant glycolysis and secretion of inflammatory cytokines, play pivotal roles in inflammatory diseases, including inflammatory bowel disease (IBD). Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors were shown to suppress Na/H exchanger 1 (NHE1) and Na/Ca exchanger 1 (NCX1) activity, regulating downstream intracellular Ca concentrations in cardiomyocytes. However, whether SGLT2 inhibitors regulate M1 macrophage polarization by downregulating NHE1 and NCX1 remains unknown.
We analyzed cellular responses to SGLT2 inhibitors using mouse bone marrow-derived macrophages and peritoneal macrophages treated with lipopolysaccharide (LPS). To induce IBD, we used a dextran sulfate sodium salt-induced colitis mouse model.
We observed that NHE1 and NCX1 were overexpressed in LPS-treated macrophages, leading to M1 macrophage polarization. Mechanistically, NHE1 and NCX1-mediated Ca accumulation in the macrophage resulted in enhanced glycolysis by promoting PI3K/AKT/mTORC1 signaling. SGLT2 inhibitors suppressed both the expression levels and activities of NHE1 and NCX1, and consequently downregulated PI3K/AKT/mTORC1 signaling and glycolysis in LPS-treated macrophages. We observed inhibition of LPS-stimulated M1 polarization and cytokine production by SGLT2 inhibitors in vitro, ex vivo, and in an IBD mouse model.
NHE1 promotes M1 macrophage polarization and SGLT2 inhibitors are a novel strategy to treat M1 macrophage-mediated inflammatory diseases, including IBD.
经典激活的 M1 巨噬细胞表现出异常的糖酵解和炎症细胞因子的分泌，在包括炎症性肠病（IBD）在内的炎症性疾病中发挥关键作用。最近，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂被证明可抑制钠/氢交换器 1（NHE1）和钠/钙交换器 1（NCX1）的活性，调节心肌细胞下游细胞内 Ca 浓度。然而，SGLT2 抑制剂是否通过下调 NHE1 和 NCX1 来调节 M1 巨噬细胞极化尚不清楚。
我们使用脂多糖（LPS）处理的小鼠骨髓来源的巨噬细胞和腹腔巨噬细胞分析 SGLT2 抑制剂的细胞反应。为了诱导 IBD，我们使用了葡聚糖硫酸钠盐诱导的结肠炎小鼠模型。
我们观察到 LPS 处理的巨噬细胞中 NHE1 和 NCX1 过表达，导致 M1 巨噬细胞极化。机制上，巨噬细胞中 NHE1 和 NCX1 介导的 Ca 积累通过促进 PI3K/AKT/mTORC1 信号转导来增强糖酵解。SGLT2 抑制剂抑制 NHE1 和 NCX1 的表达水平和活性，从而下调 LPS 处理的巨噬细胞中的 PI3K/AKT/mTORC1 信号转导和糖酵解。我们观察到 SGLT2 抑制剂在体外、在体和在 IBD 小鼠模型中抑制 LPS 刺激的 M1 极化和细胞因子产生。
NHE1 促进 M1 巨噬细胞极化，SGLT2 抑制剂是治疗 M1 巨噬细胞介导的炎症性疾病（包括 IBD）的一种新策略。
