Neuroprotective effect of alpha-kinase 1 knockdown against cerebral ischemia through inhibition of the NF-κB pathway and neuroinflammation

Jing Ying Li, Zi Xing Zheng, Lin Liu, Ou Du, Neng Wei Yu, Yunyun Zou, Seung Yong Seong, Jun Rong Du

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Activation of the nuclear factor B (NF-κB) signaling pathway by pattern recognition receptors (PRRs) is regarded as a crucial mechanism of neuroinflammation and brain injury after acute ischemic stroke. The stimulation of alpha-kinase 1 (ALPK1), a newly identified PRR, triggers NF-κB activation and an inflammatory response. Longitudinal population-based genetic epidemiological studies suggest that the ALPK1 gene is a susceptible site to ischemic stroke. However, the function of ALPK1 in the central nervous system remains unclear. The present study explored the role of ALPK1 in acute ischemic stroke. Methods: BV2 microglial cells were stimulated with conditioned medium (CM) that was collected from oxygen and glucose deprivation (OGD)-treated HT22 neurons, and a murine brain ischemia model was established to detect the changes of ALPK1 expression. We used lentivirus to knockdown ALPK1 to explore the effects of ALPK1 in cerebral ischemia models in vitro and in vivo. Results: We observed a significant increase of ALPK1 expression in BV2 cells that were stimulated with OGD CM. The knockdown of ALPK1 inhibited the phosphorylation of tumor necrosis factor receptor associated factor-interacting protein with a forkhead-associated domain (TIFA), the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), the activation of NF-κB, and the levels of proinflammatory factors in the BV2 cells. We also verified a neuroprotective effect of ALPK1 knockdown against ischemic brain injury through inhibition of the TIFA/TRAF6/NF-κB pathway and neuroinflammation in mice. Conclusions: This study demonstrates that ALPK1 is implicated in sterile inflammatory injury after acute brain ischemia, which provides first evidence for the therapeutic potential of ALPK1 inhibition in ischemic stroke.

Original languageEnglish
Article number109330
JournalInternational Immunopharmacology
Volume113
DOIs
StatePublished - Dec 2022

Keywords

  • Alpha-kinase 1 (ALPK1)
  • Ischemic stroke
  • NF-κB pathway
  • Neuroinflammation
  • pattern recognition receptor (PRR)

Fingerprint

Dive into the research topics of 'Neuroprotective effect of alpha-kinase 1 knockdown against cerebral ischemia through inhibition of the NF-κB pathway and neuroinflammation'. Together they form a unique fingerprint.

Cite this