ACT001 attenuates microglia-mediated neuroinflammation after traumatic brain injury via inhibiting AKT/NFκB/NLRP3 pathway

作者：Lin Cai, Qiuyuan Gong, Qi Lin, Tongtong Xu, Qian Suo, Xiang Li, Wei Wang, Jing Yao, Dianxu Yang, Zhiming Xu, Fang Yuan, Yaohui Tang, Guo‐Yuan Yang, Jun Ding, Hao Chen, Heng‐Li Tian · 发表于：Cell Communication and Signaling · 年份：2022 · DOI：10.1186/s12964-022-00862-y · 被引用次数：157 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Traumatic Brain Injury and Neurovascular Disturbances、S100 Proteins and Annexins

BACKGROUND: Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI. METHODS: Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments wer...