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Staphylococcus aureus is the main cause of septic arthritis in humans, a disease associated with high morbidity and mortality. Inflammation triggered in response to infection is fundamental to control bacterial growth but may cause permanent tissue damage. Here, we evaluated the role of Lipoxin A 4 (LXA 4 ) in S aureus-induced arthritis in mice. Septic arthritis was induced by S aureus injection into tibiofemoral joints. At different time points, we evaluated cell recruitment and bacterial load in the joint, the production of pro-inflammatory molecules, and LXA 4 in inflamed tissue and analyzed joint damage and dysfunction. LXA 4 was investigated using genetically modified mice or by pharmacological blockade of its synthesis and receptor. CD11c + cells were evaluated in lymph nodes by confocal microscopy and flow cytometry and dendritic cell chemotaxis using the Boyden chamber. Absence or pharmacological blockade of 5-lipoxygenase (5-LO) reduced joint inflammation and dysfunction and was associated with better control of infection at 4 to 7 days after the infection. There was an increase in LXA 4 in joints of S aureus-infected mice and administration of LXA 4 reversed the phenotype in 5-LO -/- mice. Blockade or absence of the LXA 4 receptor FPR2 has a phenotype similar to 5-LO -/- mice. Mechanistically, LXA 4 appeared to control migration and function of dendritic cells, cells shown to be crucial for adequate protective responses in the model. Thus, after the first days of infection when symptoms become evident therapies that inhibit LXA 4 synthesis or action could be useful for treatment of S aureus-induced arthritis., (© 2020 Federation of American Societies for Experimental Biology.)