{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:48:29Z","timestamp":1791895709784,"version":"4.3.4"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"31","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Complex regional pain syndrome type I (CRPS-I) develops after an initial injury. It causes prolonged pain that persists beyond the usual expected time for tissue healing. Mechanisms underlying pain chronicity of CRPS-I remain unknown. Here, we identified the presence of long-lasting infiltration of macrophages in local dorsal root ganglia (DRG) of a rat model of CRPS-I. We demonstrate that regenerating islet-derived 3\u03b2 (Reg3\u03b2) is specifically produced by DRG neurons upon model establishment and functions as an important signaling molecule to drive proinflammatory macrophage infiltration in local DRG. Infiltrated macrophages produce TNF-\u03b1, which causes hyperexcitability of nociceptive DRG neurons and reciprocally promotes Reg3\u03b2 overexpression and secretion from DRG neurons to recruit more macrophages. Our work reveals a positive feedback signaling conveyed by neuronal Reg3\u03b2\/macrophage TNF-\u03b1 that contributes to neuroinflammation in DRG, resulting in persistent pain in a rat model of CRPS-I. This finding provides insights into the neuroimmune interaction in local DRG that contributes to pain chronicity of CRPS-I.<\/jats:p>","DOI":"10.1126\/sciadv.adu4270","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T17:58:22Z","timestamp":1754071102000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Neuronal Reg3\u03b2\/macrophage TNF-\u03b1\u2013mediated positive feedback signaling contributes to pain chronicity in a rat model of CRPS-I"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6327-5613","authenticated-orcid":true,"given":"Huimin","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8801-8760","authenticated-orcid":true,"given":"Boyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5655-6292","authenticated-orcid":true,"given":"Chengyu","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."},{"name":"Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5635-4768","authenticated-orcid":true,"given":"Zishan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Hebei Medical University, Shijiazhuang, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6138-2474","authenticated-orcid":true,"given":"Yushuang","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qimiao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3267-8556","authenticated-orcid":true,"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation in Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tai","sequence":"additional","affiliation":[{"name":"Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guihua","family":"Tian","sequence":"additional","affiliation":[{"name":"Beijing Friendship Hospital, Capital Medical University, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3144-7094","authenticated-orcid":true,"given":"Chuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China."},{"name":"College of Pharmaceutical Sciences, Hebei University, Baoding, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiao","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9870-4548","authenticated-orcid":true,"given":"Boyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2018.01.004"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2018.20"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70106-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40122-021-00279-4"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac060"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4334"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13839-2"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12264-022-00910-0"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.11.015"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2233-16.2017"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1787-20.2021"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.48028"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1515\/mr-2023-0034"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2019.11.006"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.97856"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adu2159"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.3791\/60562"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S188758"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02131-0"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00453"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2020.01.007"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01834-0"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8035109"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2004.08.001"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.04.037"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2211631120"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02882-y"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.580997"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3816"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy126"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz5875"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.2174\/1876386300902010011"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-023-00491-4"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/AAP.0b013e3181958f90"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-023-02778-x"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41314"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2211-06.2006"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47640-7"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2020.12.009"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2392-04.2004"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-019-00489-1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202205397"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.41386"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.2.1066"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909086107"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.78515"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3858-05.2006"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2007.07.010"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S315774"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22137196"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1414-19.2019"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0093338"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-6-23"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1820168116"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2007.07.031"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12027"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12070"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1111\/papr.12078"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-023-03770-w"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14967"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1097\/HM9.0000000000000140"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(94)90144-9"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pa.20.040180.002301"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13760"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_3_2_68_2","doi-asserted-by":"crossref","first-page":"e0165200","DOI":"10.1371\/journal.pone.0165200","article-title":"Oxidized phospholipid OxPAPC activates TRPA1 and contributes to chronic inflammatory pain in mice","volume":"11","author":"Liu B.","year":"2016","unstructured":"B. Liu, Y. Tai, A. I. Caceres, S. Achanta, S. Balakrishna, X. Shao, J. Fang, S. E. Jordt, Oxidized phospholipid OxPAPC activates TRPA1 and contributes to chronic inflammatory pain in mice. PLOS ONE 11, e0165200 (2016).","journal-title":"PLOS ONE"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606608113"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"e_1_3_2_71_2","doi-asserted-by":"crossref","unstructured":"B. Kaminow D. Yunusov A. Dobin STARsolo: Accurate fast and versatile mapping\/quantification of single-cell and single-nucleus RNA-seq data. bioRxiv 442755 [Preprint] (2021). https:\/\/doi.org\/10.1101\/2021.05.05.442755.","DOI":"10.1101\/2021.05.05.442755"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1186\/s11658-022-00316-w"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2018.09.002"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-17-07493.2002"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI41084"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.95611"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13020-023-00800-1"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adu4270","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T17:59:01Z","timestamp":1754071141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adu4270"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":76,"journal-issue":{"issue":"31","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1126\/sciadv.adu4270"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adu4270","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"2024-11-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadu4270"}}