{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T20:58:36Z","timestamp":1793825916329,"version":"4.6.1"},"reference-count":54,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81660302"],"award-info":[{"award-number":["81660302"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    P75 pan\u2010neurotrophin receptor (p75NTR) is an important receptor for the role of neurotrophins in survival and death of neurons during development and after nerve injury. Our previous research found that the precursor of brain\u2010derived neurotrophic factor (proBDNF) regulates pain as an inflammatory mediator. The current understanding of the role of proBDNF\/p75NTR signaling pathway in inflammatory arthritis pain and rheumatoid arthritis (RA) is unclear. We recruited 20 RA patients, 20\u00a0healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&amp;E) staining and immunohistochemistry (IHC) of proBDNF and p75NTR in synovial membrane were performed and evaluated. We next examined the mRNA and protein expression of proBDNF\/p75NTR signaling pathway in peripheral blood mononuclear cells (PBMCs) and synovial tissue. ELISA and flow cytometry were assessed between the blood of RA patients and HD. To induce RA, collagen\u2010induced arthritis (CIA) were induced in mice. We found over\u2010synovitis of RA synovial membrane compared to OA controls in histologic sections. P75NTR and sortilin mRNA, and proBDNF protein level were significantly increased in PBMCs of RA patients compared with the HD. Consistently, ELISA showed that p75NTR, sortilin, tumor necrosis factor \u03b1 (TNF\u2010\u03b1), interleukin\u20101\u03b2 (IL\u20101\u03b2), interleukin\u20106 (IL\u20106), and interleukin\u201010 (IL\u201010) levels in the serum of RA patients were increased compared with HD and p75NTR, sortilin were positively correlated with Disease Activity Score in 28 joints (DAS28). In addition, using flow cytometry we showed that the increased levels of proBDNF and p75NTR characterized in CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells of RA patients were subsequently reversed with methotrexate (MTX) treatment. Furthermore, we found pathological changes, inflammatory pain, upregulation of the mRNA and protein expression of proBDNF\/p75NTR signaling pathway, and upregulation of inflammatory cytokines in spinal cord using a well\u2010established CIA mouse model. We showed intravenous treatment of recombinant p75ECD\u2010Fc that biologically blocked all inflammatory responses and relieved inflammatory pain of animals with CIA. Our findings showed the involvement of proBDNF\/p75NTR pathway in the RA inflammatory response and how blocking it with p75ECD\u2010Fc may be a promising therapeutic treatment for RA.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101558r","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T11:08:39Z","timestamp":1644232119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["proBDNF\/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0964-4641","authenticated-orcid":false,"given":"Chun\u2010Rui","family":"Yang","sequence":"first","affiliation":[{"name":"Academy of Medical Engineering and Translational Medicine Tianjin University  Tianjin P. R. China"},{"name":"Department of Pathology Tianjin Medical University Second Hospital  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Jun","family":"Ding","sequence":"additional","affiliation":[{"name":"Academy of Medical Engineering and Translational Medicine Tianjin University  Tianjin P. R. China"},{"name":"Tianjin Public Security Profession College  Tianjin P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pathology Tianjin Medical University Cancer Institute and Hospital  Tianjin P. R. 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