Abstract Introduction Sepsis, a life-threatening condition characterized by a systemic inflammatory response triggered by infection, remains one of the leading causes of mortality in intensive care units worldwide. Macrophage polarization plays a pivotal role in both the inflammatory response and tissue repair during sepsis, making it a promising target for therapeutic intervention. Regulating macrophage polarization could offer new therapies for sepsis treatment. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated potent anti-inflammatory properties, contributing to cardiovascular protection, potentially offering benefits in the management of sepsis. Objective To explore the anti-inflammatory and protective effects of SGLT2 inhibition on lipopolysaccharide-induced M1 polarization of macrophages and endothelial activation in sepsis. Method In vitro, THP-1 cells were stimulated with lipopolysaccharide (LPS) for 24 h to induce M1 macrophage polarization in the absence or presence of a 30 min pretreatment period with an SGLT2i. Gene expression levels were assessed using RT-qPCR, protein expression by Western blot analysis, reactive oxygen species (ROS) formation using dihydroethidium (DHE) staining. Additionally, porcine coronary artery endothelial cells (PCAECs) were exposed to LPS for 24 h to evaluate the surface pro-coagulant activity using a thrombin generation assay. Results Stimulation of THP-1 cells with LPS induced their polarization into M1 macrophages, which promoted upregulation of protein expression levels of the M1 protein marker (CD86) and SGLT2 associated with increased glucose uptake, formation of ROS and release of pro-inflammatory cytokines (TNF-α,IL-6,IL-1ß). However, pre-treatment with the SGLT2 inhibitor empagliflozin significantly reduced LPS-induced mRNA expression levels of ICAM-1, CCL2, IL-6, IL-1ß, iNOS and TNF-αand protein levels of CD86, p-p65 NF-kB, tissue factor, ICAM-1, and iNOS. Furthermore, SGLT2i effectively mitigated LPS-induced ROS formation in THP-1 polarized M1 macrophages and decreased glucose uptake. Notably, in LPS-exposed PCAECs, SGLT2i significantly reduced the LPS-induced surface pro-coagulant activity mediated by tissue factor, suggesting its protective role against sepsis-associated thrombosis and vascular dysfunction. Conclusions These findings highlight that LPS caused M1 polarization of macrophages promoting AT1R/NADPH oxidases/SGLT2 pro-oxidant responses and, in turn, pro-inflammatory and pro-coagulant responses. Of interest, SGLT2 inhibition mitigated the LPS-induced pro-inflammatory responses in M1 macrophages by inhibiting ROS formation and glucose uptake. Thus, SGLT2i may offer a promising therapeutic strategy, providing new clinical insights for the treatment of sepsis patients.
Yu et al. (Sat,) studied this question.