A translocator protein 18 kDa ligand, Ro5-4864, inhibits ATP-induced NLRP3 inflammasome activation.
Ro5-4864 and PK11195, prototypical synthetic ligands of translocator protein 18 kDa (TSPO), have shown anti-inflammatory effects in several models of inflammatory diseases; however, their biochemical mechanisms remain poorly understood. Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation as a part of the innate immune system, has been implicated in a variety of inflammatory diseases. Here, we demonstrate for the first time that TSPO ligands, especially Ro5-4864, potently suppressed ATP-induced NLRP3 inflammasome activation in THP-1 and BMDM cells. Detailed action mechanism was further investigated in THP-1 cells. Ro5-4864 efficiently attenuated NLRP3 translocation to mitochondria, inflammasome assembly/oligomerization, activation of caspase-1, and subsequent secretion of the mature forms of interleukin-1β and -18. Ro5-4864 also reduced the production of mitochondrial superoxide and preserved the mitochondrial membrane potential in ATP-treated cells, suggesting that Ro5-4864 may act on mitochondria or more upstream targets in NLRP3 inflammasome signaling. We also observed the distinct effects of the TSPO ligands between THP-1 monocytes and macrophages, which suggested different NLRP3 inflammasome signaling depending on cell type. Collectively, our novel findings demonstrate that Ro5-4864 effectively inhibited ATP-induced NLRP3 inflammasome activation through the prevention of mitochondrial perturbation. Our results indicate Ro5-4864 as a promising candidate for the treatment of NLRP3 inflammasome-related diseases.
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea.
Ji-Won
JW
Lee
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea.
Leah Eunjung
LE
Kim
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea.
Hyun-Jung
HJ
Shim
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea.
Eun-Kyoung
EK
Kim
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Won Chan
WC
Hwang
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Do Sik
DS
Min
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea; Neurometabolomics Research Center, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Republic of Korea. Electronic address: yusw@dgist.ac.kr.
Seong-Woon
SW
Yu
D000255:Adenosine Triphosphate / Q000276:immunology*; D001570:Benzodiazepinones / Q000008:administration & dosage*; D002478:Cells, Cultured; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008928:Mitochondria / Q000187:drug effects / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology*; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D018079:Receptors, GABA / Q000276:immunology*
D001570:Benzodiazepinones; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D018079:Receptors, GABA; C499229:TSPO protein, human; C028513:4'-chlorodiazepam; D000255:Adenosine Triphosphate
Inflammasome; Mitochondria; NLRP3; Ro5-4864; TSPO