L-Cysteine attenuates osteopontin-mediated neuroinflammation following hypoxia-ischemia insult in neonatal mice by inducing S-sulfhydration of Stat3  

作　　者：Ting-ting Li Dan-qing Xin Hong-fei Ke Xi-li Chu Yi-jing Zhao Shou-wei Yue De-xiang Liu Zhen Wang 

机构地区：[1]Department of Physiology,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Ji-nan 250012,China [2]Department of Medical Psychology and Ethics,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Ji-nan 250012,China [3]Rehabilitation Center,Qilu Hospital,Cheeloo College of Medicine,Shandong University,Ji-nan 250012,China

出　　处：《Acta Pharmacologica Sinica》2022年第7期1658-1669,共12页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(nos.82072535,81873768,and 81671213 to ZW,81772436 to SY);the Major Scientific and Technological Innovation Project in Shandong Province(2019JZZY011112 to SY).

摘　　要：We previously show that L-Cysteine administration significantly suppresses hypoxia-ischemia(HI)-induced neuroinflammation in neonatal mice through releasing H2S.In this study we conducted proteomics analysis to explore the potential biomarkers or molecular therapeutic targets associated with anti-inflammatory effect of L-Cysteine in neonatal mice following HI insult.HI brain injury was induced in postnatal day 7(P7)neonatal mice.The pups were administered L-Cysteine(5 mg/kg)at 24,48,and 72 h post-HI.By conducting TMT-based proteomics analysis,we confirmed that osteopontin(OPN)was the most upregulated protein in ipsilateral cortex 72 h following HI insult.Moreover,OPN was expressed in CD11b^(+)/CD45low cells and infiltrating CD11b^(+)/CD45^(high)cells after HI exposure.Intracerebroventricular injection of OPN antibody blocked OPN expression,significantly attenuated brain damage,reduced pro-inflammatory cytokine levels and suppressed cerebral recruitment of CD11b^(+)/CD45^(high)immune cells following HI insult.L-Cysteine administration reduced OPN expression in CD11b^(+)/CD45^(high)immune cells,concomitant with improving the behavior in Y-maze test and suppressing cerebral recruitment of CD11b^(+)/CD45^(high)immune cells post-HI insult.Moreover,L-Cysteine administration suppressed the Stat3 activation by inducing S-sulfhydration of Stat3.Intracerebroventricular injection of Stat3 siRNA not only decreased OPN expression,but also reversed HI brain damage.Our data demonstrate that L-Cysteine administration effectively attenuates the OPN-mediated neuroinflammation by inducing S-sulfhydration of Stat3,which contributes to its anti-inflammatory effect following HI insult in neonatal mice.Blocking OPN expression may serve as a new target for therapeutic intervention for perinatal HI brain injury.

关 键 词：hypoxia-ischemia brain injury L-CYSTEINE NEUROINFLAMMATION OSTEOPONTIN S-sulfhydration proteomics 

分 类 号：R741[医药卫生—神经病学与精神病学] R96[医药卫生—临床医学]