SGLT2 inhibitors prevent LPS-induced M1 macrophage polarization and alleviate inflammatory bowel disease by downregulating NHE1 expression

Inflamm Res. 2023 Nov;72(10-11):1981-1997. doi: 10.1007/s00011-023-01796-y. Epub 2023 Sep 28.

Abstract

Background: 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+/Ca2+ exchanger 1 (NCX1) activity, regulating downstream intracellular Ca2+ concentrations in cardiomyocytes. However, whether SGLT2 inhibitors regulate M1 macrophage polarization by downregulating NHE1 and NCX1 remains unknown.

Methods: 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.

Results: We observed that NHE1 and NCX1 were overexpressed in LPS-treated macrophages, leading to M1 macrophage polarization. Mechanistically, NHE1 and NCX1-mediated Ca2+ 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.

Conclusions: NHE1 promotes M1 macrophage polarization and SGLT2 inhibitors are a novel strategy to treat M1 macrophage-mediated inflammatory diseases, including IBD.

Keywords: Glycolysis; Inflammatory bowel disease; Macrophage; NHE1; SGLT2 inhibitors.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Inflammatory Bowel Diseases* / drug therapy
  • Inflammatory Bowel Diseases* / metabolism
  • Lipopolysaccharides / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors* / metabolism

Substances

  • Lipopolysaccharides
  • Sodium-Glucose Transporter 2 Inhibitors
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mechanistic Target of Rapamycin Complex 1