Article

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

Ting-ting Li1, Dan-qing Xin1, Hong-fei Ke1, Xi-li Chu1, Yi-jing Zhao1,2, Shou-wei Yue3, De-xiang Liu2, Zhen Wang1
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
Correspondence to: De-xiang Liu: liudexiang@sdu.edu.cn, Zhen Wang: wangzhen@sdu.edu.cn,
DOI: 10.1038/s41401-021-00794-2
Received: 8 June 2021
Accepted: 12 October 2021
Advance online: 4 November 2021

Abstract

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+/CD45high 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+/CD45high immune cells following HI insult. L-Cysteine administration reduced OPN expression in CD11b+/CD45high immune cells, concomitant with improving the behavior in Y-maze test and suppressing cerebral recruitment of CD11b+/CD45high 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.
Keywords: hypoxia-ischemia brain injury; L-Cysteine; neuroinflammation; osteopontin; S-sulfhydration; proteomics

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