Inhibition of lanthanide nanocrystal-induced inflammasome activation in macrophages by a surface coating peptide through abrogation of ROS production and TRPM2-mediated Ca²⁺ influx

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• 作者：Han Yao^a ; Yunjiao Zhang^a ; ^b ; ^{yunjiaoz@ustc.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Liu Liu^a ; Youcui Xu^a ; Xi Liu^a ; Jun Lin^a ; ^b ; Wei Zhou^a ; ^b ; Pengfei Wei^a ; ^b ; ^{pfwei@mail.ustc.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Peipei Jin^a ; Long-Ping Wen^a ; ^b ; ^{lpwen@ustc.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Lanthanide-based nanoparticles (LNs) ; NLRP3 inflammasome ; RE-1 peptide ; ROS generation ; Ca2+ influx ; TRPM2
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：108
• 期：Complete
• 页码：143-156
• 全文大小：3355 K

文摘

Lanthanide-based nanoparticles (LNs) hold great promise in medicine. A variety of nanocrystals, including LNs, elicits potent inflammatory response through activation of NLRP3 inflammasome. We have previously identified an LNs-specific surface coating peptide RE-1, with the sequence of ‘ACTARSPWICG’, which reduced nanocrystal-cell interaction and abrogated LNs-induced autophagy and toxicity in both HeLa cells and liver hepatocytes. Here we show that RE-1 coating effectively inhibited LNs-induced inflammasome activation, mostly mediated by NLRP3, in mouse bone marrow derived macrophage (BMDM) cells, human THP-1 cells and mouse peritoneal macrophages and also reduced LNs-elicited inflammatory response in vivo. RE-1 coating had no effect on cellular internalization of LNs in BMDM cells, in contrast to the situation in HeLa cells where cell uptake of LNs was significantly inhibited by RE-1. To elucidate the molecular mechanism underlying the inflammasome-inhibiting effect of RE-1, we assessed several parameters known to influence nanocrystal-induced NLRP3 inflammasome activation. RE-1 coating did not reduce potassium efflux, which occurred after LNs treatment in BMDM cells and was necessary but insufficient for LNs-induced inflammasome activation. RE-1 did decrease lysosomal damage induced by LNs, but the inhibitor of cathepsin B did not affect LNs-elicited caspase 1 activation and IL-1β release, suggesting that lysosomal damage was not critically important for LNs-induced inflammasome activation. On the other hand, LNs-induced elevation of intracellular reactive oxygen species (ROS), critically important for inflammasome activation, was largely abolished by RE-1 coating, with the reduction on NADPH oxidase-generated ROS playing a more prominent role for RE-1's inflammasome-inhibiting effect than the reduction on mitochondria-generated ROS. ROS generation further triggered Ca²⁺ influx, an event that was mediated by Transient Receptor Potential M2 (TRPM2) and was necessary for inflammasome activation, and this event was completely inhibited by RE-1 coating. We conclude from these studies that inhibition of ROS production, and the subsequent abrogation of TRPM2-mediated Ca²⁺ influx, is the primary mechanism underlying RE-1's inhibitory effect on LNs-induced inflammasome activation. The ability of regulating the inflammatory response of nanocrystals through peptide surface coating may be of great value for in vivo applications of LNs and other engineered nanomaterials.