PMID- 33573688 OWN - NLM STAT- MEDLINE DCOM- 20211229 LR - 20240226 IS - 1478-811X (Electronic) IS - 1478-811X (Linking) VI - 19 IP - 1 DP - 2021 Feb 11 TI - Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. PG - 13 LID - 10.1186/s12964-020-00647-1 [doi] LID - 13 AB - BACKGROUND: Epimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI. METHODS: Bone-marrow-derived macrophages (BMDMs) were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1beta (IL-1beta) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo. RESULTS: Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mouse model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation. CONCLUSIONS: Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI. Video abstract. FAU - Gao, Yuan AU - Gao Y AD - School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Xu, Guang AU - Xu G AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Ma, Li AU - Ma L AD - School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China. FAU - Shi, Wei AU - Shi W AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Wang, Zhilei AU - Wang Z AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Zhan, Xiaoyan AU - Zhan X AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Qin, Nan AU - Qin N AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - He, Tingting AU - He T AD - Integrative Medical Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China. FAU - Guo, Yuming AU - Guo Y AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Niu, Ming AU - Niu M AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Wang, Jiabo AU - Wang J AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. FAU - Bai, Zhaofang AU - Bai Z AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. baizf2008@hotmail.com. FAU - Xiao, Xiaohe AU - Xiao X AD - China Military Institute of Chinese Materia, the Fifth Medical Centre, Chinese PLA General Hospital, No. 100 Xisihuan, Beijing, 100039, China. pharmacy_302@126.com. AD - Integrative Medical Center, the Fifth Medical Centre, Chinese PLA General Hospital, Beijing, 100039, China. pharmacy_302@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210211 PL - England TA - Cell Commun Signal JT - Cell communication and signaling : CCS JID - 101170464 RN - 0 (Flavones) RN - 0 (Furans) RN - 0 (IL1B protein, mouse) RN - 0 (Indenes) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Reactive Oxygen Species) RN - 0 (Sulfonamides) RN - 0 (Tnf protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Umbelliferones) RN - 0 (icariside I) RN - 6RS86E2BWQ (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 1.1.1.27 (L-Lactate Dehydrogenase) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 3.4.22.36 (Casp1 protein, mouse) RN - EC 3.4.22.36 (Caspase 1) RN - RRU6GY95IS (Nigericin) SB - IM MH - *Adenosine Triphosphate MH - Alanine Transaminase/blood MH - Animals MH - Aspartate Aminotransferases/blood MH - Caspase 1/immunology MH - *Chemical and Drug Induced Liver Injury/blood/immunology/metabolism MH - Female MH - Flavones/*toxicity MH - Furans/pharmacology MH - Indenes/pharmacology MH - Inflammasomes/antagonists & inhibitors/*immunology MH - Interleukin-1beta/blood MH - L-Lactate Dehydrogenase/*toxicity MH - Lipopolysaccharides MH - Macrophages/drug effects/immunology/metabolism MH - Mice, Inbred C57BL MH - Mitochondria/drug effects/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/*immunology MH - *Nigericin MH - Reactive Oxygen Species/metabolism MH - Sulfonamides/pharmacology MH - Tumor Necrosis Factor-alpha/blood MH - Umbelliferones/*toxicity MH - Mice PMC - PMC7879676 OTO - NOTNLM OT - Epimedii folium OT - Icariside I OT - Idiosyncratic drug-induced liver injury OT - NLRP3 inflammasome COIS- The authors declare that they have no conflicts of interest to disclose. The study was approved by the Experimental Animal Center of Chinese PLA General Hospital, Beijing, China. All procedures followed were in accordance with the ethical standards of the Ethics Committee of the Chinese PLA General Hospital and the Helsinki Declaration of 1975. The authors declare that they have no conflicts of interests. EDAT- 2021/02/13 06:00 MHDA- 2021/12/30 06:00 PMCR- 2021/02/11 CRDT- 2021/02/12 05:40 PHST- 2019/11/23 00:00 [received] PHST- 2020/08/12 00:00 [accepted] PHST- 2021/02/12 05:40 [entrez] PHST- 2021/02/13 06:00 [pubmed] PHST- 2021/12/30 06:00 [medline] PHST- 2021/02/11 00:00 [pmc-release] AID - 10.1186/s12964-020-00647-1 [pii] AID - 647 [pii] AID - 10.1186/s12964-020-00647-1 [doi] PST - epublish SO - Cell Commun Signal. 2021 Feb 11;19(1):13. doi: 10.1186/s12964-020-00647-1.