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

Abstract

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 γ-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.

• Authors: Yujun Xu, Yi Li, Xinghan Liu, Yuchen Pan, Zhiheng Sun, Yaxian Xue, Tingting Wang, Huan Dou, Yayi Hou
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 14 Pg. 6779-6797 ( 2019) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 31692534 (Publication Type: Journal Article)
• Copyright: © 2019 Xu et al.

Chemical References

• Cav1 protein, mouse
• Caveolin 1
• Ferric Compounds
• Hes1 protein, mouse
• IL10 protein, mouse
• Lipopolysaccharides
• Magnetite Nanoparticles
• Notch1 protein, mouse
• Receptor, Notch1
• Transcription Factor HES-1
• Interleukin-10
• ferric oxide

Topics

• Animals
• Autophagy (drug effects, physiology)
• Caveolin 1 (genetics, metabolism)
• Ferric Compounds (chemistry, pharmacology)
• Interleukin-10 (metabolism)
• Lipopolysaccharides (toxicity)
• Liver (drug effects, metabolism, pathology)
• Macrophages (drug effects, metabolism, pathology)
• Magnetite Nanoparticles (chemistry, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• RAW 264.7 Cells
• Receptor, Notch1 (metabolism)
• Sepsis (drug therapy, metabolism, pathology)
• Transcription Factor HES-1 (metabolism)