Simultaneous neutralization of TGF-β and IL-6 attenuates S. aureus induced arthritic inflammation through differential modulation of splenic and synovial macrophages.

Septic arthritis is a joint disease caused by Staphylococcus aureus (S. aureus). Different macrophage populations contribute in various ways to control blood-borne infections and induce inflammatory responses. Macrophage tissue-resident 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 regulates the inflammatory consequences. Aim of this study is to find out the mechanism by which neutralization of TGF-β and/or IL-6 after induction of septic arthritis could alter the specific macrophage responses in spleen and synovial joints via different cytokine (OPG, OPN, IL-10, IL-12, and CXCL8) cross-talking, and how the response could be modulated by ROS versus antioxidant enzyme activities. Dual neutralization of TGF-β and IL-6 is notably effective in eliciting splenic and synovial tissue-resident macrophage responses. Synovial macrophage-derived IL-10 can elicit protection against septic arthritis via regulating 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-β and IL-6 prevented bone destruction and osteoclastic activity in septic arthritis by promoting the differential functional response of the splenic and synovial macrophages. Additionally, the macrophage-derived IL-10 can elicit protection against S. aureus induced septic arthritis via regulating RANKL/OPG interaction. Further studies on STAT3 and STAT4 are needed for the understanding of such cross-talking in resident macrophages of arthritic mice.