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

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.

Immunohistochemical Evaluation of Aquaporin-4 and its Correlation with CD68, IBA-1, HIF-1α, GFAP, and CD15 Expressions in Fatal Traumatic Brain Injury

“…The presence of AQP4 seems to play an acute detrimental role, but at a later phase starting from around seven days post injury and for at least one month. AQP4 may play a beneficial role that seems to be related to the inhibition of microglia and promotion of edema resolution [ 60 , 61 , 62 , 63 ].…”

AQP4 Attenuated TRAF6/NFκB Activation in Acrylamide-Induced Neurotoxicity

“…In a postmortem study, patients with depression exhibited lower AQP4 mRNA and protein expression in the brain than healthy control [ 16 , 17 ]. AQP4 knockout also revealed negative effects on neuroprotective markers and behavioral outcomes and was associated with increases in inflammatory markers in animal models of depression [ 18 ], indicating that AQP4 exhibits neuroprotective functions in the CNS and against MDD. MMP-9, a proteolytic enzyme related to synaptic plasticity in the brain activates proinflammatory cytokines in neuroinflammation and is released by T cells during immunoreactions [ 19 ].…”

Spatiotemporal Expression of SphK1 and S1PR2 in the Hippocampus of Pilocarpine Rat Model and the Epileptic Foci of Temporal Lobe Epilepsy

“…Recent studies have verified that SphK1 is implicated in the process of inflammation and causes chronic neuroinflammation ( Melendez, 2008 ; Dai et al, 2018 ). Importantly, a recent study has reported that upregulates the SphK1/S1P receptor signaling pathway may be a key factor of astrocytes mediated chronic inflammation in multiple sclerosis, and BBR ameliorated the severity of MS symptom in mouse model through inducing the increase in SphK1 and S1P.…”