Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway

• DOI: 10.1016/j.fct.2021.112591
• Publication Date: 2021-10-04T17:14:51Z
• Authors: Wudi Hao; Chenyu Hao; Chengrong Wu; Yuqing Xu; Shengwen Wu; Xiaobo Lu; Jinghua Yang; Cuihong Jin
• Keywords: Cerebral Cortex; 0301 basic medicine; 0303 health sciences; Inflammasomes; Blotting, Western; Fluorescent Antibody Technique; Real-Time Polymerase Chain Reaction; 3. Good health; DEAD-box RNA Helicases; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cognition; Hindlimb Suspension; Microscopy, Electron, Transmission; Blood-Brain Barrier; Morris Water Maze Test; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Aluminum Chloride; Animals; Aluminum; Signal Transduction

Aluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet.The mice model of subacute exposure to aluminum chloride (AlCl3) was established. BV2 microglia cells was treated with AlCl3 in vitro. Resveratrol (Rsv) was adopted as intervention agent.Our results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1β and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent.Aluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1).