AQP4‑knockout alleviates the lipopolysaccharide‑induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling

Dai,Wangshu; Yan,Junjun; Chen,Guangzong; Hu,Gang; Zhou,Xiqiao; Zeng,Xiaoning

doi:10.3892/ijmm.2018.3749

AQP4‑knockout alleviates the lipopolysaccharide‑induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling

Authors:
- Wangshu Dai
- Junjun Yan
- Guangzong Chen
- Gang Hu
- Xiqiao Zhou
- Xiaoning Zeng
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Affiliations: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R.China, Department of Gastroenterology, The First People's Hospital of Jiujiang, Jiujiang, Jiangxi 332000, P.R.China , Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R.China, Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: June 29, 2018 https://doi.org/10.3892/ijmm.2018.3749
Pages: 1716-1722

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Abstract

To date, aquaporin‑4 (AQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen‑activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4+/+ and AQP4‑/‑ embryos, the production of tumor necrosis factor‑α (TNF‑α)/interleukin‑6 (IL‑6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF‑α/IL‑6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4‑/‑ group compared with that in the AQP4+/+ group. Although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the AQP4‑/‑ genotype. The phosphorylation of MAPK/AKT was also confirmed to be attenuated in the AQP4‑/‑ group, suggesting decreased MAPK/AKT signaling over time in AQP4‑/‑ astrocytes. Overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/MAPK/AKT pathway. This data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.

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