PMID- 38086268 OWN - NLM STAT- MEDLINE DCOM- 20240118 LR - 20240118 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 127 DP - 2024 Jan 25 TI - Activation of mitochondrial DNA-mediated cGAS-STING pathway contributes to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord. PG - 111348 LID - S1567-5769(23)01675-2 [pii] LID - 10.1016/j.intimp.2023.111348 [doi] AB - Chronic postsurgical pain (CPSP) is increasingly recognized as a public health issue. Recent studies indicated the innate immune pathway of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) was involved in pain regulation. However, the detailed mechanisms remain unclear. Previous studies found A1 reactive astrocytes in the spinal cord contributed to CPSP. This study aimed to investigate the roles and mechanisms of the cGAS-STING pathway in regulating the generation of A1 reactive astrocytes during CPSP. First, CPSP model was established using skin/muscle incision and retraction (SMIR) in rats. We found that cGAS-STING pathway was activated accompanied with an increase in mitochondrial DNA in the cytosol in the spinal cord following SMIR. Second, a STING inhibitor C-176 was intrathecally administrated. We found that C-176 decreased the expression of type I interferons and A1 reactive astrocytes in the spinal cord, and alleviated mechanical allodynia in SMIR rats. Third, cyclosporin A as a mitochondrial permeability transition pore blocker was intrathecally administrated. We found that cyclosporin A decreased the leakage of mitochondrial DNA and inhibited the activation of cGAS-STING pathway. Compared with C-176, cyclosporin A exhibits similar analgesic effects. The expression of type I interferons and A1 reactive astrocytes in the spinal cord were also down-regulated after intervention with cyclosporin A. Moreover, simultaneous administration of cyclosporin A and C-176 did not show synergistic effects in SMIR rats. Therefore, our study demonstrated that the cGAS-STING pathway activated by the leakage of mitochondrial DNA contributed to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Chen, Yuye AU - Chen Y AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Hu, Yingjie AU - Hu Y AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - He, Xiao AU - He X AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Zang, Hu AU - Zang H AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Sun, Rao AU - Sun R AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Zhu, Chang AU - Zhu C AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. FAU - Yao, Wenlong AU - Yao W AD - Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: wlyao82@126.com. LA - eng PT - Journal Article DEP - 20231211 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Interferon Type I) RN - 0 (DNA, Mitochondrial) RN - 83HN0GTJ6D (Cyclosporine) RN - EC 2.7.7.- (Nucleotidyltransferases) SB - IM MH - Rats MH - Animals MH - *Interferon Type I/metabolism MH - DNA, Mitochondrial/metabolism MH - Astrocytes/metabolism MH - Cyclosporine MH - Spinal Cord/metabolism MH - Nucleotidyltransferases/genetics/metabolism MH - Pain, Postoperative OTO - NOTNLM OT - A1 reactive astrocytes OT - Chronic postsurgical pain OT - Cyclic guanosine monophosphate-adenosine monophosphate synthase OT - Interferon OT - Mitochondrial permeability transition pore OT - Stimulator of interferon gene 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- 2023/12/13 00:41 MHDA- 2024/01/18 06:42 CRDT- 2023/12/12 18:08 PHST- 2023/09/05 00:00 [received] PHST- 2023/11/18 00:00 [revised] PHST- 2023/12/04 00:00 [accepted] PHST- 2024/01/18 06:42 [medline] PHST- 2023/12/13 00:41 [pubmed] PHST- 2023/12/12 18:08 [entrez] AID - S1567-5769(23)01675-2 [pii] AID - 10.1016/j.intimp.2023.111348 [doi] PST - ppublish SO - Int Immunopharmacol. 2024 Jan 25;127:111348. doi: 10.1016/j.intimp.2023.111348. Epub 2023 Dec 11.