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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2020.tde-21022020-133020
Document
Author
Full name
Ayda Henriques Schneider
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2019
Supervisor
Committee
Cunha, Fernando de Queiroz (President)
Farsky, Sandra Helena Poliselli
Amaral, Flávio Almeida
Title in Portuguese
Papel das NETs como indutoras de dor articular na artrite reumatoide
Keywords in Portuguese
Artrite reumatoide
Dor articular
NETs
Neutrófilos
Abstract in Portuguese
A artrite reumatoide (AR) é uma doença autoimune que tem como um dos principais sintomas a dor articular. Durante o processo inflamatório, nociceptores são ativados por mediadores nociceptivos, como por exemplo a prostaglandina E2 e via IL-1?. É conhecido o papel fundamental dos neutrófilos na liberação de estímulos nociceptivos, entretanto, não é conhecido o papel das neutrophil extracellular traps liberadas por esses neutrófilos em doenças autoimunes como a artrite, na gênese da dor articular. Nossos resultados demonstraram que animais com artrite induzida por antígeno (AIA) possuem um aumento de NETs relacionado com o aumento da expressão gênica de Pad4, enzima fundamental para a geração de NETs. A degradação dessas NETs através de DNase é capaz de reduzir parâmetros da doença, como o edema, hiperplasia da sinóvia, infiltrado celular, e a hipernocicepção, apesar de não haver alteração na migração dos neutrófilos para as articulações. A partir disso, nossos resultados seguintes demonstraram que as NETs são capazes de induzir hipernocicepção em camundongos e que essa queda no limiar mecânico pode ocorrer devido aumento da expressão de COX-2, o que possivelmente leva a uma ativação de prostaglandinas. Além disso, ocorre aumento da concentração de citocinas pró- inflamatórias, possivelmente via ativação de receptores Toll-4 pelo reconhecimento das histonas dessas NETs. Ademais, pacientes com AR possuem aumento de NETs nos líquidos sinoviais e neutrófilos mais propensos a produzirem NETs, as quais têm relação com o aumento da escala de dor nesses pacientes. Deste modo, podemos propor um novo alvo para o tratamento de dor articular.
Title in English
Role of NETs as inducers of joint pain in rheumatoid arthritis
Keywords in English
Joint pain
NETs
Neutrophils
Rheumatoid arthritis
Abstract in English
Rheumatoid arthritis (RA) is an autoimmune disease that has as one of the main joint symptoms. During the inflammatory process, nociceptors are activated by nociceptive media, such as prostaglandin E2 and via IL-1?. The role of neutrophils in the release of nociceptive stimuli is known, however, the role of neutrophil extracellular traps released by these neutrophils in autoimmune diseases as an arthritis in the origin of joint pain is not known. Our results demonstrated that animals with antigen-induced arthritis (AIA) have an increase in NETs related to the increase in Pad4 gene expression, a fundamental enzyme for the generation of NETs. Degradation of these NETs through DNase can reduce disease levels such as edema, synovial hyperplasia, cellular infiltrate and hypernociception, although there is no change in neutrophils to joints. From this, our results demonstrated as NETs are able to induce hypernociception in mice and that probably no mechanical mechanism limit may occur the increased expression of COX-2, or leading to prostaglandin. In addition, there is an increased concentration of proinflammatory cytokines, possibly via activation of Toll-4 receptors by recognizing the histories of these NETs. In addition, RA patients have increased NETs at synovial and neutrophil levels more likely to produce NETs, as they are related to increasing patient scale. In this mode we can propose a new target for the treatment of joint pain.
 
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Publishing Date
2020-05-04
 
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