Neutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation

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dc.creatorAyda Henriques Schneider
dc.creatorSandra Yasuyo Fukada
dc.creatorPaulo Louzada-Júnior
dc.creatorTarcília Aparecida da Silva
dc.creatorFernando Queiroz Cunha
dc.creatorCaio Cavalcante Machado
dc.creatorFlávio Protásio Veras
dc.creatorAlexandre Gomes de Macedo Maganin
dc.creatorFlávio Falcão Lima de Souza
dc.creatorLívia Corrêa Barroso
dc.creatorRenê Donizeti Ribeiro de Oliveira
dc.creatorJosé Carlos Alves-Filho
dc.creatorThiago Mattar Cunha
dc.date.accessioned2025-04-14T19:19:03Z
dc.date.accessioned2025-09-09T01:04:12Z
dc.date.available2025-04-14T19:19:03Z
dc.date.issued2021-07
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.description.sponsorshipFAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1093/rheumatology/keaa794
dc.identifier.issn1462-0332
dc.identifier.urihttps://hdl.handle.net/1843/81561
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofRheumatology
dc.rightsAcesso Restrito
dc.subjectHyperalgesia
dc.subjectExtracellular traps
dc.subjectNeutrophils
dc.subjectArthritis, rheumatoid
dc.subjectPain
dc.subjectGene expression
dc.subjectEvaluation study
dc.subjectCytokines
dc.subjectReceptors, tumor necrosis factor, type I
dc.subjectReceptors, interleukin-1 type I
dc.subjectToll-like Receptor 4
dc.subjectToll-like receptor 9
dc.subjectSynovial fluid
dc.subjectCyclooxygenase 2
dc.subject.otherNETs
dc.subject.otherHyperalgesia
dc.subject.otherNeutrophils
dc.subject.otherRheumatoid arthritis
dc.titleNeutrophil extracellular traps mediate joint hyperalgesia induced by immune inflammation
dc.typeArtigo de periódico
local.citation.epage3473
local.citation.issue7
local.citation.spage3461
local.citation.volume60
local.description.resumoObjective: To evaluate the role of neutrophil extracellular traps (NETs) in the genesis of joint hyperalgesia using an experimental model of arthritis and transpose the findings to clinical investigation. Methods: C57BL/6 mice were subjected to antigen-induced arthritis (AIA) and treated with Pulmozyme (PLZ) to degrade NETs or Cl-amidine to inhibit NET production. Oedema formation, the histopathological score and mechanical hyperalgesia were evaluated. NETs were injected intra-articularly in wild type (WT), Tlr4-/-, Tlr9-/-, Tnfr1-/- and Il1r-/- mice, and the levels of cytokines and Cox2 expression were quantified. NETs were also quantified from human neutrophils isolated from RA patients and individual controls. Results: AIA mice had increased NET concentration in joints, accompanied by increased Padi4 gene expression in the joint cells. Treatment of AIA mice with a peptidyl arginine deiminase 4 inhibitor or with PLZ inhibited the joint hyperalgesia. Moreover, the injection of NETs into joints of naïve animals generated a dose-dependent reduction of mechanical threshold, an increase of articular oedema, inflammatory cytokine production and cyclooxygenase-2 expression. In mice deficient for Tnfr1, Il1r, Tlr4 and Tlr9, joint hyperalgesia induced by NETs was prevented. Last, we found that neutrophils from RA patients were more likely to release NETs, and the increase in synovial fluid NET concentration correlated with an increase in joint pain. Conclusion: The findings indicate that NETs cause hyperalgesia possibly through Toll-like receptor (TLR)-4 and TLR-9. These data support the idea that NETs contribute to articular pain, and this pathway can be an alternative target for the treatment of pain in RA.
local.identifier.orcidhttps://orcid.org/0000-0003-2474-2773
local.identifier.orcidhttps://orcid.org/0000-0002-6589-4784
local.identifier.orcidhttps://orcid.org/0000-0003-2585-3870
local.identifier.orcidhttps://orcid.org/0000-0001-9623-7835
local.identifier.orcidhttps://orcid.org/0000-0003-4755-1670
local.identifier.orcidhttps://orcid.org/0000-0002-6222-4064
local.identifier.orcidhttps://orcid.org/0000-0002-4838-3800
local.identifier.orcidhttps://orcid.org/0000-0002-7558-0172
local.identifier.orcidhttps://orcid.org/0000-0001-8422-5538
local.identifier.orcidhttps://orcid.org/0000-0003-0229-6864
local.identifier.orcidhttps://orcid.org/0000-0002-9918-8714
local.identifier.orcidhttps://orcid.org/0000-0002-7855-3700
local.identifier.orcidhttps://orcid.org/0000-0003-1619-1959
local.publisher.countryBrasil
local.publisher.departmentFAO - DEPARTAMENTO DE CLÍNICA
local.publisher.initialsUFMG
local.url.externahttps://academic.oup.com/rheumatology/article/60/7/3461/6050618?login=true

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