La goutte est une arthrite particulièrement douloureuse due à une réponse immunitaire contre des cristaux d’urate monosodique (MSU). Le neutrophile est un leucocyte qui contribue grandement à la perpétuation de l’inflammation lors d’une crise de goutte. Avant d’être recrutés au site d’inflammation, les neutrophiles rencontrent plusieurs médiateurs pro-inflammatoires, dont la protéine S100A9. Nous montrons ici que S100A9 accentue plusieurs réponses effectrices des neutrophiles humains aux MSU, notamment la production de dérivés réactifs de l’oxygène (ROS), la sécrétion de CXCL8/IL-8 et d’IL-1β et la glycolyse. S100A9 augmente également la mobilisation intracellulaire de calcium du neutrophile en plus d’augmenter la phosphorylation des tyrosines, la phosphorylation des sérines des substrats de la PKC, d’AKT et de la p38. Nous avons identifié un des mécanismes par lesquels S100A9 contribue à la pathogenèse de la goutte ainsi que les voies de signalisation impliquées dans ce phénomène qui sont des cibles thérapeutiques potentielles pour cette maladie. / Gout is the common and painful type of inflammatory arthritis. It is caused by an immune response against monosodium urate crystals (MSU) that form in the affected joint. Neutrophils are the most abundant leukocytes in the gout joint and play a key role in perpetuating inflammation during a gout flare. During their recruitment to the site of inflammation, neutrophils are exposed to several pro-inflammatory mediators such as S100A9. Although blocking S100A9 dampens MSU-induced inflammation, the role of this protein in the pathogenesis of gout remains incompletely characterized. We identified a novel role for S100A9 in MSU-induced inflammation, the priming of neutrophils towards MSU activation. We provide evidence for the ability of S100A9 to enhance several effector functions of human neutrophils triggered by MSU including the production of reactive oxygen species (ROS), the secretion of CXCL8/IL-8 and IL-1β as well as glycolysis. As for intracellular signaling, S100A9 increases the mobilisation of calcium, induces tyrosine phosphorylation of intracellular proteins as well as serine phosphorylation of PKC, AKT and p38 kinase. In summary, we report for the first time that S100A9 acts as a priming agent during MSU-induced inflammation and identify the underlying signaling pathways that could be targeted to treat gout.
| Identifer | oai:union.ndltd.org:LAVAL/oai:corpus.ulaval.ca:20.500.11794/28324 |
| Date | 09 May 2020 |
| Creators | Rousseau, Louis-Simon |
| Contributors | Fernandes, Maria J., Pelletier, Martin |
| Source Sets | Université Laval |
| Language | French |
| Detected Language | French |
| Type | mémoire de maîtrise, COAR1_1::Texte::Thèse::Mémoire de maîtrise |
| Format | 1 ressource en ligne (x,88 pages), application/pdf |
| Rights | http://purl.org/coar/access_right/c_abf2 |
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