PMID- 36418508 OWN - NLM STAT- MEDLINE DCOM- 20230524 LR - 20230524 IS - 1434-9949 (Electronic) IS - 0770-3198 (Linking) VI - 42 IP - 6 DP - 2023 Jun TI - AIM2 and NLRC4-driven inflammasome activation in adult-onset Still's disease and the preliminary therapeutic effect exploration of carboxyamidotriazole. PG - 1635-1643 LID - 10.1007/s10067-022-06443-1 [doi] AB - OBJECTIVES: This study aimed to explore the changes of four major inflammasomes in adult-onset Still's disease (AOSD) and preliminarily evaluate the therapeutic effect of carboxyamidotriazole (CAI), which has previously been reported to have the significant anti-inflammatory activity. METHOD: The mRNA expressions of proinflammatory cytokines and inflammasome components in peripheral blood mononuclear cells (PBMCs) from AOSD patients and healthy controls (HC) were determined by reverse transcription-quantitative PCR. Poly(dA:dT)-induced AIM2 inflammasome and flagellin-induced NLRC4 inflammasome activation models were established in bone marrow-derived macrophages (BMDMs). The levels of cytokines in serum and culture supernatants were measured by ELISA method. RESULTS: The serum levels of IL-1beta, IL-6, and TNF-alpha in AOSD patients were significantly higher than those in HC. However, the mRNA expressions of IL-1beta, IL-6, IL-18, and TNF-alpha in PBMCs did not differ markedly in AOSD patients in comparison with HC. Significantly increased mRNA levels of AIM2, NLRC4, ASC, and caspase-1 were observed in patients with AOSD when compared with HC, while NLRP1 and NLRP3 showed no change in AOSD samples. In addition, CAI treatment could significantly reduce the levels of IL-1beta, IL-6, and TNF-alpha secreted by AOSD PBMCs and inhibit AIM2 and NLRC4 inflammasomes activation in BMDMs. CONCLUSIONS: Increased levels of proinflammatory cytokines in AOSD might be associated with NLRC4 and AIM2 inflammasomes activation. CAI is likely to have the therapeutic potential for AOSD by inhibiting NLRC4 and AIM2 inflammasomes activation and reducing the proinflammatory cytokines and worthy of further investigation. These results provide new ideas for elucidating the pathogenesis of AOSD and providing specific targeted therapy. Key points * Significantly higher mRNA levels of AIM2 and NLRC4 inflammsome signaling were observed in AOSD patients compared with health controls, indicating that AIM2 and NLRC4 inflammsome activation might be related to the increased proinflammatory cytokines in AOSD. * CAI treatment markedly reduced the secretion levels of cytokines IL-1beta, IL-6, and TNF-alpha in AOSD PBMCs and inhibited AIM2 and NLRC4 inflammasome activation. CI - (c) 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR). FAU - Duan, Mengyuan AU - Duan M AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - Shen, Min AU - Shen M AD - Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH); Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, 100730, Beijing, China. FAU - Zhou, Yongting AU - Zhou Y AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - He, Yi AU - He Y AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - Guo, Zehao AU - Guo Z AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - Ye, Caiying AU - Ye C AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - Li, Juan AU - Li J AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. FAU - Zhu, Lei AU - Zhu L AUID- ORCID: 0000-0003-3471-1663 AD - Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China. leizhu2004@126.com. LA - eng PT - Journal Article DEP - 20221124 PL - Germany TA - Clin Rheumatol JT - Clinical rheumatology JID - 8211469 RN - 0 (Inflammasomes) RN - 6ST3ZF52WB (carboxyamido-triazole) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Interleukin-6) RN - 0 (Cytokines) RN - 0 (Interleukin-1beta) RN - 0 (RNA, Messenger) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRC4 protein, human) RN - 0 (Calcium-Binding Proteins) RN - 0 (CARD Signaling Adaptor Proteins) RN - 0 (AIM2 protein, human) RN - 0 (DNA-Binding Proteins) SB - IM MH - Adult MH - Humans MH - *Inflammasomes/metabolism MH - *Still's Disease, Adult-Onset MH - Tumor Necrosis Factor-alpha/metabolism MH - Interleukin-6/metabolism MH - Leukocytes, Mononuclear/metabolism MH - Cytokines/metabolism MH - Interleukin-1beta/metabolism MH - RNA, Messenger/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Calcium-Binding Proteins MH - CARD Signaling Adaptor Proteins/metabolism MH - DNA-Binding Proteins OTO - NOTNLM OT - Adult-onset Still's disease OT - Carboxyamidotriazole OT - Cytokines OT - Inflammasome EDAT- 2022/11/24 06:00 MHDA- 2023/05/24 06:42 CRDT- 2022/11/23 23:37 PHST- 2022/02/01 00:00 [received] PHST- 2022/11/02 00:00 [accepted] PHST- 2022/10/13 00:00 [revised] PHST- 2023/05/24 06:42 [medline] PHST- 2022/11/24 06:00 [pubmed] PHST- 2022/11/23 23:37 [entrez] AID - 10.1007/s10067-022-06443-1 [pii] AID - 10.1007/s10067-022-06443-1 [doi] PST - ppublish SO - Clin Rheumatol. 2023 Jun;42(6):1635-1643. doi: 10.1007/s10067-022-06443-1. Epub 2022 Nov 24.