PMID- 38340422 OWN - NLM STAT- MEDLINE DCOM- 20240226 LR - 20240226 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 129 DP - 2024 Mar 10 TI - Geraniin restricts inflammasome activation and macrophage pyroptosis by preventing the interaction between ASC and NLRP3 to exert anti-inflammatory effects. PG - 111656 LID - S1567-5769(24)00174-7 [pii] LID - 10.1016/j.intimp.2024.111656 [doi] AB - Geraniin, a chemical component of the traditional Chinese medicine geranii herba, possesses anti-inflammatory and anti-oxidative activities. However, its anti-inflammatory role in managing NLRP3 inflammasome and pyroptosis remains to be elucidated. To investigate the anti-inflammation mechanism of geraniin, LPS-primed macrophages were incubated with classical activators of NLRP3 inflammasome (such as ATP, Nigericin, or MSU crystals), and MSU crystals were injected into the ankle joints of mice to establish an acute gouty arthritis model. The propidium iodide (PI) staining results showed that geraniin could restrain cell death in the ATP- or nigericin-stimulated bone marrow-derived macrophages (BMDMs). Geraniin decreased the release of lactate dehydrogenase (LDH) and interleukin (IL)-1beta from cytoplasm to cell supernatant. Geraniin also inhibited the expression of caspase-1 p20, IL-1beta in cell supernatant and N-terminal of gasdermin D (GSDMD-NT) while blocking the oligomerization of ASC to form speck. The inhibitory effects of geraniin on caspase-1 p20, IL-1beta, GSDMD-NT, and ASC speck were not observed in NLRP3 knockout (NLRP3(-/-)) BMDMs. Hence, the resistance of geraniin to inflammasome and pyroptosis was contingent upon NLRP3 presence. Geraniin reduced reactive oxygen species (ROS) production and maintained mitochondrial membrane potential while preventing interaction between ASC and NLRP3 protein. Additionally, geraniin diminished MSU crystal-induced mouse ankle joint swelling and IL-1beta expression. Geraniin blocked the recruitment of neutrophils and macrophages to the synovium of joints. Our results demonstrate that geraniin prevents the assembly of ASC and NLRP3 through its antioxidant effect, thereby inhibiting inflammasome activation, pyroptosis, and IL-1beta release to provide potential insights for gouty arthritis targeted therapy. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Zhou, Xiaoyi AU - Zhou X AD - Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - Qin, Minyan AU - Qin M AD - Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - He, Leran AU - He L AD - Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - Zhang, Ying AU - Zhang Y AD - Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - Liu, Aijun AU - Liu A AD - Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - Chen, Dongfeng AU - Chen D AD - Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. FAU - Pan, Hao AU - Pan H AD - Department of Human Anatomy, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China; Research Centre for Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China. Electronic address: hao.pan25@foxmail.com. LA - eng PT - Journal Article DEP - 20240209 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 60976-49-0 (Geraniin) RN - RRU6GY95IS (Nigericin) RN - 0 (Anti-Inflammatory Agents) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 3.4.22.- (Caspases) RN - 0 (Interleukin-1beta) RN - 0 (Glucosides) RN - 0 (Hydrolyzable Tannins) SB - IM MH - Mice MH - Animals MH - *Inflammasomes/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - *Arthritis, Gouty/chemically induced MH - Pyroptosis MH - Nigericin/pharmacology MH - Macrophages MH - Anti-Inflammatory Agents/adverse effects MH - Adenosine Triphosphate/metabolism MH - Caspases/metabolism MH - Interleukin-1beta/metabolism MH - *Glucosides MH - *Hydrolyzable Tannins OTO - NOTNLM OT - ASC OT - Geraniin OT - Gouty arthritis OT - NLRP3 inflammasome OT - Pyroptosis COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/02/11 07:42 MHDA- 2024/02/26 06:42 CRDT- 2024/02/10 18:02 PHST- 2023/11/02 00:00 [received] PHST- 2024/01/24 00:00 [revised] PHST- 2024/02/01 00:00 [accepted] PHST- 2024/02/26 06:42 [medline] PHST- 2024/02/11 07:42 [pubmed] PHST- 2024/02/10 18:02 [entrez] AID - S1567-5769(24)00174-7 [pii] AID - 10.1016/j.intimp.2024.111656 [doi] PST - ppublish SO - Int Immunopharmacol. 2024 Mar 10;129:111656. doi: 10.1016/j.intimp.2024.111656. Epub 2024 Feb 9.