Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia

小胶质细胞 炎症体 神经科学 BETA(编程语言) β淀粉样蛋白 淀粉样蛋白(真菌学) 化学 TLR4型 细胞生物学 免疫学 医学 生物 炎症 病理 疾病 计算机科学 程序设计语言
作者
Jing Wang,Yue Dai,Qing Li,Chen Chen,Hao Chen,Yuanjian Song,Fang Hua,Zuohui Zhang
出处
期刊:Neuroscience Letters [Elsevier]
卷期号:736: 135279-135279 被引量:111
标识
DOI:10.1016/j.neulet.2020.135279
摘要

Beta-amyloid(Aβ)-induced inflammation plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) inflammasome is involved in the Aβ-induced inflammation. However, the mechanisms by which extracellular Aβ activates cytoplasmic NLRP3 inflammasome are poorly understood. Toll-like receptor 4(TLR4) acts as a sensor of Aβ and performs a key role in neuroinflammation. TLR4 is involved in activating the NLRP3 inflammasome in several diseases. In this study, the interaction between TLR4 and NLRP3 inflammasome in Aβ1−42-induced neuroinflammation was investigated. BV-2 microglia and primary microglia were primed with lipopolysaccharide (LPS) and then pretreated with TLR4 inhibitor CLI-095, followed by stimulation with Aβ1–42. The protein expression of NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 p 10 was detected by western blotting and immunostaining. The mRNA expression of inflammatory factors was measured by real-time PCR. The protein level of pro IL-1β and IL-1β was examined by ELISA. Activated microglia were examined by immunofluorescence staining for ionized calcium-binding adapter molecule-1 (Iba-1). Conditioned medium of BV-2 cells was collected to challenge HT-22 neurons. Cell viability was assessed with MTT assay. Assessment of HT-22 cell apoptosis was performed by Annexin V/PI staining and western blotting to detect the protein level of cleaved caspase 3. The results showed that Aβ1−42 activated and up-regulated the expression of NLRP3 inflammasome in BV-2 microglia, as indicated by increased activation of caspase-1 and secretion of IL-1β. Pharmacological inhibition of TLR4 by CLI-095 abolished Aβ1−42-induced NLRP3 inflammasome activation, which curbed the development of inflammation and exerted protective effect on HT-22 neurons. Furthermore, the inhibitory effects of CLI-095 on Aβ1−42-induced inflammation were reversed by NLRP3 activator ATP. Overall, our findings suggested TLR4 mediated Aβ1−42-induced NLRP3 inflammasome activation in mouse microglia. TLR4/NLRP3 pathway plays a critical role in Aβ1−42-induced neuroinflammation.
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