proBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines

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dc.contributor.authorYang, C.R.
dc.contributor.authorDing, H.J.
dc.contributor.authorYu, M.
dc.contributor.authorZhou, F.H.
dc.contributor.authorHan, C.Y.
dc.contributor.authorLiang, R.
dc.contributor.authorZhang, X.Y.
dc.contributor.authorZhang, X.L.
dc.contributor.authorMeng, F.J.
dc.contributor.authorWang, S.
dc.contributor.authorLi, D.D.
dc.contributor.authorSun, W.Z.
dc.contributor.authorMeng, B.
dc.contributor.authorZhou, X.F.
dc.date.issued2022
dc.description.abstractP75 pan-neurotrophin 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-derived 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 healthy donors (HDs), and 10 osteoarthritis (OA) patients. Hematoxylin and eosin (H&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-induced arthritis (CIA) were induced in mice. We found over-synovitis 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 α (TNF-α), interleukin-1β (IL-1β), interleukin- 6 (IL-6), and interleukin-10 (IL-10) 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⁺ and CD8⁺ 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-established CIA mouse model. We showed intravenous treatment of recombinant p75ECD-Fc 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-Fc may be a promising therapeutic treatment for RA.
dc.description.statementofresponsibilityChun-Rui Yang, Hong-Jun Ding, Miao Yu, Fiona-H. Zhou, Chen-Yang Han, Rui Liang, Xiao-Yang Zhang, Xiang-Lian Zhang, Fan-Jie Meng, Shuo Wang, De-Dong Li, Wei-Zong Sun, Bin Meng, Xin-Fu Zhou
dc.identifier.citationThe FASEB Journal, 2022; 36(3):e22180-1-e22180-21
dc.identifier.doi10.1096/fj.202101558R
dc.identifier.issn0892-6638
dc.identifier.issn1530-6860
dc.identifier.orcidZhou, F.H. [0000-0003-3113-1671]
dc.identifier.orcidZhou, X.F. [0000-0002-8687-0175]
dc.identifier.urihttps://hdl.handle.net/2440/146447
dc.language.isoen
dc.publisherWiley
dc.rights© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.source.urihttps://doi.org/10.1096/fj.202101558r
dc.subjectinflammation; p75NTR; pain; proBDNF; rheumatoid arthritis
dc.subject.meshSynovial Membrane
dc.subject.meshLeukocytes, Mononuclear
dc.subject.meshT-Lymphocytes
dc.subject.meshAnimals
dc.subject.meshMice, Inbred C57BL
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshArthritis, Rheumatoid
dc.subject.meshBrain-Derived Neurotrophic Factor
dc.subject.meshTumor Necrosis Factor-alpha
dc.subject.meshReceptors, Nerve Growth Factor
dc.subject.meshNerve Tissue Proteins
dc.subject.meshProtein Precursors
dc.subject.meshInterleukins
dc.subject.meshAdult
dc.subject.meshMiddle Aged
dc.subject.meshFemale
dc.subject.meshMale
dc.titleproBDNF/p75NTR promotes rheumatoid arthritis and inflammatory response by activating proinflammatory cytokines
dc.typeJournal article
pubs.publication-statusAccepted

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