Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangdong Technological Engineering Research Center for Pets, College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, People's Republic of China.
Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangdong Technological Engineering Research Center for Pets, College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province 510642, People's Republic of China.
J Hazard Mater. 2022 Aug 15;436:129093. doi: 10.1016/j.jhazmat.2022.129093. Epub 2022 May 10.
Combined exposure of chronic stress and alumina nanoparticles (AlNPs) aggravates hippocampal injury, but the pathogenesis is unevaluated. This study aimed to investigate the effect and mechanism of co-exposure to chronic stress and AlNPs on hippocampal microglia pyroptosis. In this study, chronic restraint stress (CRS) alone caused NLRP3-mediated hippocampal microglia pyroptosis, but AlNPs did not. Moreover, co-exposure to CRS and AlNPs exacerbated hippocampal microglia pyroptosis, resulting in more severe hippocampal damage and behavioral deficits in rats. Protein-protein interaction network predicted that cathepsin B was a potential regulatory protein of NLRP3. CRS up-regulated cathepsin B expression which had a more pronounced increase in co-exposure group. Whereas, caspase-1 inhibitor VX-765 alleviated hippocampal microglia pyroptosis and behavioral deficits in rats. Consistent with in vivo results, co-exposure of corticosterone and AlNPs aggravated NLRP3-mediated pyroptosis and cathepsin B expression in HAPI cells. Nevertheless, the pyroptosis of HAPI cells was inhibited by cathepsin B inhibitor CA-074Me and NLRP3 knockout, respectively. NLRP3 agonist nigericin failed to promote the pyroptosis of HAPI cells in the presence of cathepsin B inhibition. These results demonstrated that co-exposure to chronic stress and AlNPs could aggravate hippocampal microglia pyroptosis by activating cathepsin B/NLRP3 signaling pathway, resulting in hippocampal damage and behavioral deficits.
慢性应激和氧化铝纳米颗粒（AlNPs）联合暴露加重海马损伤，但发病机制尚未评估。本研究旨在探讨慢性应激和 AlNPs 联合暴露对海马小胶质细胞焦亡的影响及机制。在这项研究中，单独的慢性束缚应激（CRS）导致 NLRP3 介导的海马小胶质细胞焦亡，但 AlNPs 没有。此外，CRS 和 AlNPs 的联合暴露加剧了海马小胶质细胞焦亡，导致大鼠海马损伤更严重，行为缺陷更明显。蛋白质-蛋白质相互作用网络预测组织蛋白酶 B 是 NLRP3 的潜在调节蛋白。CRS 上调组织蛋白酶 B 的表达，在联合暴露组中表达增加更为明显。然而，半胱天冬酶-1 抑制剂 VX-765 缓解了大鼠海马小胶质细胞焦亡和行为缺陷。与体内结果一致，皮质酮和 AlNPs 的联合暴露加重了 HAPI 细胞中 NLRP3 介导的焦亡和组织蛋白酶 B 的表达。然而，组织蛋白酶 B 抑制剂 CA-074Me 和 NLRP3 敲除分别抑制了 HAPI 细胞的焦亡。在组织蛋白酶 B 抑制存在的情况下，NLRP3 激动剂 Nigericin 未能促进 HAPI 细胞的焦亡。这些结果表明，慢性应激和 AlNPs 的联合暴露通过激活组织蛋白酶 B/NLRP3 信号通路加重海马小胶质细胞焦亡，导致海马损伤和行为缺陷。
