AQP4­knockout alleviates the lipopolysaccharide­induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling.

ABSTRACT

To date, aquaporin­4 (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/mitogen­activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4+/+ and AQP4­/­ embryos, the production of tumor necrosis factor­α (TNF­α)/interleukin­6 (IL­6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF­α/IL­6 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.