PMID- 37660594 OWN - NLM STAT- Publisher LR - 20231017 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 124 IP - Pt A DP - 2023 Nov TI - ASIC1a-CMPK2-mediated M1 macrophage polarization exacerbates chondrocyte senescence in osteoarthritis through IL-18. PG - 110878 LID - S1567-5769(23)01203-1 [pii] LID - 10.1016/j.intimp.2023.110878 [doi] AB - PURPOSE: Identification of a role for, and the mechanism of action of, the acid-sensing ion channel 1a (ASIC1a) in M1 macrophage polarization, which results in osteoarthritis (OA)-associated chondrocyte senescence. METHOD: ASIC1a expression in synovial M1 macrophages of OA patients was assessed by immunofluorescence. A role for ASIC1a in M1 macrophage and chondrocyte senescence was assessed in a mouse OA model. RESULTS: ASIC1a expression was found to be upregulated in synovial M1 macrophages of OA patients. Extracellular acidification (pH 6.0) promoted M1 polarization of bone marrow derived macrophages (BMDMs), which was reversed by PcTx-1 or ASIC1a-siRNA. RNA-seq transcriptome results demonstrated a downregulation of M1 macrophage-associated genes in BMDMs after PcTx-1 treatment. Mechanistically, a role for the ASIC1a-cytidine/uridine monophosphate kinase 2 (CMPK2) axis in M1 macrophage polarization was demonstrated. The concentration of IL-18 was elevated in synovial fluid and supernatants of acid-activated BMDMs. In vitro, IL-18 stimulation or co-culture with acid-activated macrophages promoted chondrocyte senescence. In vivo, intra-articular administration of PcTx-1 reduced articular cartilage destruction and chondrocytes senescence in OA mice, which related to reduced numbers of M1 macrophages and IL-18 in affected joints. CONCLUSION: These results demonstrate a novel pathogenic process that results in OA cartilage damage, in which M1 macrophage derived IL-18 induces articular chondrocytes senescence. Further, the ASIC1a-CMPK2 axis was shown to positively regulate M1 macrophage polarization. Hence, ASIC1a is a promising treatment target for M1 macrophage-mediated diseases, such as OA. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Dong, Lei AU - Dong L AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. FAU - Zhao, Yingjie AU - Zhao Y AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Sun, Cheng AU - Sun C AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. FAU - Ou Yang, Ziwei AU - Ou Yang Z AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. FAU - Chen, Fan AU - Chen F AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Hu, Weirong AU - Hu W AD - The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Zhang, Hailin AU - Zhang H AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Wang, Yan AU - Wang Y AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Zhu, Rendi AU - Zhu R AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. FAU - Cheng, Yuanzhi AU - Cheng Y AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. FAU - Chen, Yong AU - Chen Y AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. FAU - Li, Shufang AU - Li S AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. FAU - Wang, Ke AU - Wang K AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. FAU - Ding, Changhai AU - Ding C AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. FAU - Zhou, Renpeng AU - Zhou R AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China. Electronic address: zhourenpeng@ahmu.edu.cn. FAU - Hu, Wei AU - Hu W AD - Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: huwei@ahmu.edu.cn. LA - eng PT - Journal Article DEP - 20230901 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 SB - IM OTO - NOTNLM OT - ASIC1a OT - Chondrocytes OT - IL-18 OT - M1 macrophage OT - Osteoarthritis OT - Senescence 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- 2023/09/04 00:41 MHDA- 2023/09/04 00:41 CRDT- 2023/09/03 18:09 PHST- 2023/01/30 00:00 [received] PHST- 2023/08/25 00:00 [revised] PHST- 2023/08/28 00:00 [accepted] PHST- 2023/09/04 00:41 [pubmed] PHST- 2023/09/04 00:41 [medline] PHST- 2023/09/03 18:09 [entrez] AID - S1567-5769(23)01203-1 [pii] AID - 10.1016/j.intimp.2023.110878 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Nov;124(Pt A):110878. doi: 10.1016/j.intimp.2023.110878. Epub 2023 Sep 1.