Involvement of ADAM10 in acrolein-induced astrocytic inflammation. (January 2020)

• Record Type: Journal Article
• Authors: Park, Jung Hyun; Choi, Ji-Young; Jo, Chulman; Koh, Young Ho
• Is Part Of: Toxicology letters. Volume 318(2020)
• Page Start: 44
• Page End: 49
• Publication Date: 2020-01
• Subjects: Acrolein -- ADAM10 -- Astrocyte -- Inflammation -- NLRP3; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.10.005
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: Acrolein induces astrocytic inflammation. ADAM10 plays a key role in acrolein –induced NLRP3 inflammasome. Acrolein responsible for ADAM10 activation leads to astrocytic dysfunction. Abstract: Acrolein is a neurotoxin produced through lipid peroxidation in the brain affected by ischemic stroke, which results in neuronal cell injury and inflammation. However the mechanism underlying acrolein-induced brain inflammation remains unclear. Therefore we examined how acrolein leads to astrocytic inflammation. It was found that acrolein increased the levels of NLRP3 and cleaved caspase-1, which led to the maturation of interleukin-1β (IL-1β). ELISA assay results, which showed that acrolein increased the secreted IL-1β, further supported acrolein-induced astrocytic inflammation. Acrolein increased ADAM10 protein levels and the cleavage of N-cadherin. The ADAM10 inhibitor, GI 254023X blocked N-cadherin cleavage by acrolein, suggesting that ADAM10 is an upstream of N-cadherin. Furthermore, we found that acrolein activated p38 MAPK and NF-κB p65, while pretreatment with p38 MAPK inhibitor, SB203580 and GI 254023X inhibited NF-κB p65 activation and NLRP3 inflammasome. This suggests that p38 MAPK mediates the activation of NF-κB p65, which is associated with NLRP3 expression. Finally, we showed that acrolein induced cell toxicity and decrease of EAAT1 expression, suggesting that acrolein may induce a loss of glutamate uptake function. In conclusion, we demonstrate that acrolein induces astrocytic inflammation through NLRP3 inflammasome, which is regulated by ADAM10 and attributed to p38 MAPK-activated NF-κB p65 activity.