SPIONs enhances IL-10-producing macrophages to relieve sepsis via Cav1-Notch1/HES1-mediated autophagy

Background: Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Macrophages, which recognize microbial infections through identification of bacterial markers such as lipopolysaccharide (LPS), are crucial to the pathogenesis of sepsis-associated liver injury. However, the understanding of the SPIONs-mediated modulation of macrophage responses in LPS-induced sepsis and liver injury is limited. Materials and methods: Superparamagnetic iron oxide nanoparticles (SPIONs) of gamma-Fe2O3 nanoparticles were prepared, and their morphology and magnetic properties were characterized. Results: Using a murine model of LPS-induced sepsis and liver injury, we found that SPIONs alleviated LPS-induced sepsis, preventing infiltration of inflammatory cells into the liver. SPIONs also increased the level of interleukin-10 (IL-10) in liver macrophages, while SPIONs's effect on LPS-induced sepsis was abrogated in IL-10(-/-) mice, indicating that the protective effect of SPIONs is dependent on IL-10(+) macrophages. Moreover, SPIONs activated macrophage autophagy to increase IL-10 production, which was markedly attenuated by autophagy inhibition. Furthermore, SPIONs upregulated the expression of Caveolin-1 (Cav1) in macrophages, which plays a role in cellular uptake of metallic nanoparticles. Interestingly, activation of Cav1 and Notch1/HES1 signaling was involved in SPIONs-induced autophagy in both RAW 264.7 cells and bone marrow-derived macrophages (BMDMs). Our data reveal a novel mechanism for SPIONs -induced autophagy in macrophages, which occurs through activation of the Cav1-Notch1/HES1 signaling pathway, which promotes the production of IL-10 in macrophages, leading to inhibition of inflammation in LPS-induced sepsis and liver injury. Conclusion: Our results suggest that SPIONs may represent a potential therapeutic agent for the treatment of sepsis and sepsis-induced liver injury.