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Macrophage tissue\u2013resident niche is necessary for the suppression of chronic inflammation and may contribute to the pathogenesis of septic arthritis. Thus, to obtain a resolution of the disease and restoration of synovial homeostasis, it needs the activation of macrophages that further regulate the inflammatory consequences. The aim of this study was to find out the mechanism by which neutralization of transforming growth factor\u2010beta (TGF\u2010\u03b2) and\/or interleukin (IL)\u20106 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokines (osteoprotegerin (OPG), osteopontin (OPN), IL\u201010, IL\u201012 and CXCL8) cross\u2010talking, and how the response could be modulated by reactive oxygen species vs antioxidant enzyme activities. Dual neutralization of TGF\u2010\u03b2 and IL\u20106 is notably effective in eliciting splenic and synovial tissue\u2013resident macrophage responses. Synovial macrophage\u2010derived IL\u201010 can elicit protection against septic arthritis via regulating receptor\u2010activated nuclear factor Kappa\u2010B ligand (RANKL)\/OPG interaction. They also reduced oxidative stress by increasing the activity of antioxidant enzymes including SOD and catalase. Histopathological analysis revealed that dual neutralization of TGF\u2010\u03b2 and IL\u20106 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage\u2010derived IL\u201010 can elicit protection against <jats:italic>S.\u00a0aureus<\/jats:italic>\u2010induced septic arthritis via regulating RANKL\/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross\u2010talking in resident macrophages of arthritic mice.<\/jats:p>","DOI":"10.1111\/sji.13252","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T05:37:05Z","timestamp":1672810625000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Simultaneous neutralization of <scp>TGF<\/scp>\u2010\u03b2 and <scp>IL<\/scp>\u20106 attenuates <i>Staphylococcus aureus<\/i>\u2010induced arthritic inflammation through differential modulation of splenic and synovial macrophages"],"prefix":"10.1111","volume":"97","author":[{"given":"Rituparna","family":"Ghosh","sequence":"first","affiliation":[{"name":"Immunology Laboratory, Department of Physiology University of Calcutta, University Colleges of Science and Technology  Calcutta West Bengal 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