S100A9 Upregulation Contributes to Learning and Memory Impairments by Promoting Microglia M1 Polarization in Sepsis Surv
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ORIGINAL ARTICLE
S100A9 Upregulation Contributes to Learning and Memory Impairments by Promoting Microglia M1 Polarization in Sepsis Survivor Mice Yan-Ling Liao,1,2 Xiao-Yan Zhou,1 Mu-Huo Ji,3 Liang-Cheng Qiu,4 Xiao-Hui Chen,2 Can-Sheng Gong,2 Ying Lin,2 Yan-Hua Guo,2 and Jian-Jun Yang 1,3,5 (Received May 20, 2020; accepted August 25, 2020)
Abstract— Sepsis-associated encephalopathy (SAE) is a clinical syndrome of brain dysfunction
secondary to sepsis, which is characterized by long-term neurocognitive deficits such as memory, attention, and executive dysfunction. However, the mechanisms underlying SAE remain unclear. By using transcriptome sequencing approach, we showed that hippocampal S100A9 was significantly increased in sepsis induced by cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) challenge. Thus, we used S100A9 inhibitor Paquinimod to study the role of S100A9 in cognitive impairments in CLP-induced and LPS-induced mice models of SAE. Sepsis survivor mice underwent behavioral tests or the hippocampal tissues subjected to Western blotting, real-time quantitative PCR, and immunohistochemistry. Our results showed that CLP-induced and LPS-induced memory impairments were accompanied with increased expressions of hippocampal microglia Iba1 and CD86 (M1 markers), but reduced expression of Arg1 (M2 marker). Notably, S100A9 inhibition significantly improved the survival rate and learning and memory impairments in sepsis survivors, with a shift from M1 to M2 phenotype. Taken together, our study suggests that S100A9 upregulation might contribute to learning and memory impairments by promoting microglia M1 polarization in sepsis survivors, whereas S100A9 inhibition might provide a potential therapeutic target for SAE. KEY WORDS: sepsis-associated encephalopathy; cognition; microglia; S100A9; neuroinflammation.
Yan-Ling Liao and Xiao-Yan Zhou contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-020-01334-6) contains supplementary material, which is available to authorized users. 1
Department of Anesthesiology, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, 21002, China 2 Department of Anesthesiology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
3
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China 4 Department of Anesthesiology, Fujian Provincial Jinshan Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350004, China 5 To whom correspondence should be addressed at Department of Anesthesiology, Jinling Hospital, Jinling School of Clinical Medicine, Nanjing Medical University, Nanjing, 21002, China. E-mail: [email protected]
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Liao, Zhou, Ji, Qiu, Chen, Gong, Lin, Guo, and Yang INTRODUCTION Sepsis
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