PMID- 31692534 OWN - NLM STAT- MEDLINE DCOM- 20200203 LR - 20220411 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 14 DP - 2019 TI - SPIONs enhances IL-10-producing macrophages to relieve sepsis via Cav1-Notch1/HES1-mediated autophagy. PG - 6779-6797 LID - 10.2147/IJN.S215055 [doi] AB - 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-Fe(2)O(3) 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. CI - (c) 2019 Xu et al. FAU - Xu, Yujun AU - Xu Y AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Li, Yi AU - Li Y AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Liu, Xinghan AU - Liu X AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Pan, Yuchen AU - Pan Y AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Sun, Zhiheng AU - Sun Z AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Xue, Yaxian AU - Xue Y AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Wang, Tingting AU - Wang T AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. AD - Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Dou, Huan AU - Dou H AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. AD - Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. FAU - Hou, Yayi AU - Hou Y AD - The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. AD - Jiangsu Key Laboratory of Molecular Medicine, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, People's Republic of China. LA - eng PT - Journal Article DEP - 20190823 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Cav1 protein, mouse) RN - 0 (Caveolin 1) RN - 0 (Ferric Compounds) RN - 0 (Hes1 protein, mouse) RN - 0 (IL10 protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (Magnetite Nanoparticles) RN - 0 (Notch1 protein, mouse) RN - 0 (Receptor, Notch1) RN - 0 (Transcription Factor HES-1) RN - 130068-27-8 (Interleukin-10) RN - 1K09F3G675 (ferric oxide) SB - IM MH - Animals MH - Autophagy/*drug effects/physiology MH - Caveolin 1/genetics/metabolism MH - Ferric Compounds/chemistry/pharmacology MH - Interleukin-10/metabolism MH - Lipopolysaccharides/toxicity MH - Liver/drug effects/metabolism/pathology MH - Macrophages/*drug effects/metabolism/pathology MH - Magnetite Nanoparticles/chemistry/*therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - RAW 264.7 Cells MH - Receptor, Notch1/metabolism MH - Sepsis/*drug therapy/metabolism/pathology MH - Transcription Factor HES-1/metabolism PMC - PMC6711564 OTO - NOTNLM OT - IL-10 OT - SPIONs OT - autophagy OT - liver injury OT - sepsis COIS- The authors report no conflicts of interest in this work. EDAT- 2019/11/07 06:00 MHDA- 2020/02/06 06:00 PMCR- 2019/08/23 CRDT- 2019/11/07 06:00 PHST- 2019/05/09 00:00 [received] PHST- 2019/07/28 00:00 [accepted] PHST- 2019/11/07 06:00 [entrez] PHST- 2019/11/07 06:00 [pubmed] PHST- 2020/02/06 06:00 [medline] PHST- 2019/08/23 00:00 [pmc-release] AID - 215055 [pii] AID - 10.2147/IJN.S215055 [doi] PST - epublish SO - Int J Nanomedicine. 2019 Aug 23;14:6779-6797. doi: 10.2147/IJN.S215055. eCollection 2019.