2. Academic Validation
  3. Role of nuclear factor of activated T Cells-1 in Sepsis-induced behavioral deficits in mice

Role of nuclear factor of activated T Cells-1 in Sepsis-induced behavioral deficits in mice

  • Brain Res. 2023 Feb 24;1806:148299. doi: 10.1016/j.brainres.2023.148299.
Fan Jiang 1,  Yaoyi Guo 1,  Liang Hu 2,  Mengxue Zhang 3,  Jieqiong Meng 1,  Yanna Si 4,  Hongwei Shi 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China.
  • 2 Department of Pharmacology, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 3 Department of Pathology, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 4 Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China. Electronic address: siyanna@163.com.
  • 5 Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, Jiangsu, China. Electronic address: mdshw@163.com.
PMID: 36842570 DOI: 10.1016/j.brainres.2023.148299
Abstract

Introduction: The nuclear factor of activated T cells-1 (NFAT1) is involved in both neuroinflammation and cognitive dysfunction. In this study, we examined the role of NFAT1 in sepsis-induced cognitive impairment in a mouse model.

Methods: Sepsis was established in adult mice by cecal ligation and puncture (CLP). Novel object recognition tests on days 14-21 and fear conditioning tests on days 22-23 post-surgery showed that CLP impaired both behaviors. BV2 microglia cells exposed to lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting NFAT1 on Autophagy and inflammatory cytokines.

Results: CLP increased the expression of NFAT1 in hippocampal microglia and induced hippocampal Autophagy by downregulating p62, upregulating beclin-1 and autophagy-related gene-5, and increasing the ratio of microtubule-associated protein 1 light chain 3-I (LC3-I) to LC3-II. In addition, CLP shifted microglial polarization from M2 to M1 and the production of inflammatory cytokines, similar to the effects of lipopolysaccharide on BV2 microglia cells. Conversely, NFAT1 knockdown or the Autophagy Inhibitor 3-methyladenine attenuated the effects of CLP on Autophagy and inflammation in vitro and in vivo, while rapamycin partially reversed the protective effects of NFAT1 inhibition.

Conclusion: This study suggests that NFAT1 downregulation attenuates sepsis-induced behavioral deficits by inhibiting Autophagy, microglia polarization, and neuroinflammation..

Keywords

Autophagy; Hippocampus; NFAT1; Neuroinflammation; Sepsis-associated encephalopathy.

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