{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:12:20Z","timestamp":1789143140220,"version":"build-2803163510"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T00:00:00Z","timestamp":1769644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82130121"],"award-info":[{"award-number":["No. 82130121"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The acupuncture acupoint is the critical initial site for the therapeutic efficacy of electroacupuncture (EA). Previous studies have confirmed that the NF-\u03baB pathway within the acupoint region mediates the therapeutic effects of acupuncture. Therefore, this study focuses on an in-depth investigation of the MD2\/TLR4\/NF-\u03baB axis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The mouse model of adjuvant-induced arthritis (AIA) was established via intraplantar injection of Complete Freund\u2019s Adjuvant (CFA). EA intervention was applied bilaterally to the Zusanli (ST36) acupoints, and behavioral, molecular, and immunological approaches were integrated to investigate the role of MD2 in EA-mediated analgesia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      EA increased paw thermal withdrawal thresholds (PTWTs) in AIA mice (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), accompanied by higher levels of MD2, TLR4, p65, and the phosphorylated form of p65 (p-p65) at the acupoint. Co-immunoprecipitation (Co-IP) confirmed binding between MD2 and TLR4 in ST36 acupoint, while immunofluorescence (IF) revealed co-localization of TLR4 with fibroblasts and mast cells in ST36, suggesting these immune cells are critical targets for signal activation. Lentivirus-mediated knockdown of MD2 in the acupoint partially reversed EA\u2019s analgesic effects and suppressed downstream TLR4\/NF-\u03baB pathway activation, whereas MD2 overexpression elicited a partial analgesic effect and promoted pathway activation. Together with spinal cord proteomics data, these findings indicate that modulating MD2 in the acupoint can regulate spinal cord-related signaling pathways. Mechanistically, EA dynamically regulates the equilibrium of the Grem1\/BMP4\/COX2 axis in the spinal dorsal horn via activation of the MD2\/TLR4\/NF-\u03baB pathway cascade, achieving systemic analgesia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides molecular evidence supporting the \"acupoint priming\" theory in acupuncture and highlights MD2 as a potential therapeutic target for pain management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1626755","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:23:20Z","timestamp":1769664200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Electroacupuncture alleviates pain by activating the MD2\/TLR4\/NF-\u03baB pathway in the ST36 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Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifang","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"National Clinical Research Center for Chinese Medicine","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine","place":["Tianjin, China"]},{"name":"Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine","place":["Tianjin, 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