上睑下垂
细胞生物学
炎症
TLR4型
细胞外
化学
信号转导
生物
免疫学
炎症体
作者
Yuan Xu,Xin An,Lei Liu,Xinran Cao,Zhanfeng Wu,Wang Jia,Jiacheng Sun,Haoyu Wang,Jiawei Huo,Zihao Sun,Mingming Zhen,Chunru Wang,Chunli Bai
出处
期刊:ACS Nano
[American Chemical Society]
日期:2024-01-10
卷期号:18 (3): 2131-2148
标识
DOI:10.1021/acsnano.3c09397
摘要
Endotoxemia is a life-threatening multiple organ failure disease caused by bacterial endotoxin infection. Unfortunately, current single-target therapy strategies have failed to prevent the progression of endotoxemia. Here, we reported that alanine fullerene redox modulator (AFRM) remodeled the intestinal microenvironment for multiple targets endotoxemia mitigation by suppressing inflammatory macrophages, inhibiting macrophage pyroptosis, and repairing epithelial cell barrier integrity. Specifically, AFRM exhibited broad-spectrum and self-cascade redox regulation properties with superoxide dismutase (SOD)-like enzyme, peroxidase (POD)-like enzyme activity, and hydroxyl radical (•OH) scavenging ability. Guided by proteomics, we demonstrated that AFRM regulated macrophage redox homeostasis and down-regulated LPS/TLR4/NF-κB and MAPK/ERK signaling pathways to suppress inflammatory hyperactivation. Of note, AFRM could attenuate inflammation-induced macrophage pyroptosis via inhibiting the activation of gasdermin D (GSDMD). In addition, our results revealed that AFRM could restore extracellular matrix and cell-tight junction proteins and protect the epithelial cell barrier integrity by regulating extracellular redox homeostasis. Consequently, AFRM inhibited systemic inflammation and potentiated intestinal epithelial barrier damage repair during endotoxemia in mice. Together, our work suggested that fullerene based self-cascade redox modulator has the potential in the management of endotoxemia through synergistically remodeling the inflammation and epithelial barriers in the intestinal microenvironment.
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