Control of infection versus articular damage: role of neutrophils and 5- lipoxygenase in septic arthritis
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Universidade Federal de Minas Gerais
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Tese de doutorado
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Membros da banca
Angélica Thomaz Vieira
Graciela Andrei
Fabiana Simão Machado
Adriana Maria Kakchasi
Graciela Andrei
Fabiana Simão Machado
Adriana Maria Kakchasi
Resumo
Staphylococcus aureus is the main pathogen associated with septic arthritis. Upon infection, neutrophils are quickly recruited to the joint by different chemoattractants, such as chemokines and leukotriene B4 (LTB4). Although their excessive accumulation is associated with intense pain and permanent articular damage, neutrophils have an important function in controlling bacterial burden. This work aimed to study the role of chemokines and the enzyme 5-lipoxygenase (5-LO) in the control of infection, hypernociception, and tissue damage in S. aureus-induced septic arthritis in mice. The blockade of the chemokine receptors CXCR1/2 from the beginning of infection decreased neutrophil accumulation in S. aureus-infected joint, contributing to the reduction of articular damage and hypernociception, although it increased the bacterial load. CXCR1/2 was important for the killing of S. aureus by purified human neutrophils. The later start of the treatment did not increase the bacterial load, but only transiently decreased hypernociception and did not improved tissue damage. Using another strategy, we blocked the chemokine binding to glycosaminoglycans (GAGs) by intravenously injection of CXCL9 (74-103). Although this treatment decreased neutrophil accumulation in peptidoglycan- and S. aureus-infected joints, during infection it was not effective to reduce articular damage and hypernociception and increased the bacterial load. In another set of experiments, 5-lipoxygenase (LO)-/- mice had a reduced neutrophil accumulation, joint damage, hypernociception, and bacterial load 7 days after S. aureus injection compared to wild type (WT) mice. At day 4, there were increased numbers of activated cluster of differentiation 11c (CD11c)+ cells and T lymphocytes in the joint and draining lymph node of 5-LO-/- compared to WT mice. At this time point, there was an increase of lipoxin A4 (LXA4)/LTB4 ratio in the joint, two byproducts from 5-LO activity. The blockade of the LXA4 surface receptor, ALX/formyl peptide receptor (FPR)2, in WT mice decreased the bacterial load in infected joints. Corroborating, the injection of LXA4 in 5-LO-/- mice increased the number of recovered bacteria. Interestingly, LXA4-treated human dendritic cells decreased chemotaxis under CCL21 stimulation. In conclusion, the blockade of CXCR1/2, chemokine-GAG binding and LXA4 activity could be useful for the improvement of current treatment of S. aureus-induced arthritis by different mechanisms, but commonly by decreasing neutrophil recruitment.
Abstract
Assunto
Artrite, Staphylococcus aureus, Quimiocinas, Araquidonato 5-lipoxigenase, Receptores de lipoxinas
Palavras-chave
Arthritis, Staphylococcus aureus, Chemokines, 5-lipoxygenase, Lipoxin A4
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