Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation

摘要

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial,and its role in patients with S.aureus osteomyelitis is unknown.To address this knowledge gap,we completed a clinical study and observed elevated serum IL-27 levels(20-fold higher,P<0.05)in patients compared with healthy controls.Remarkably,IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients(P<0.05),suggesting a pathogenic role of IL-27.To test this hypothesis,we evaluated S.aureus osteomyelitis in WT and IL-27Rα^(−/−)mice with and without exogenous IL27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP,respectively.We found that IL-27 was induced at the surgical site within 1 day of S.aureus infection of bone and was expressed by M0,M1 and M2 macrophages and osteoblasts but not by osteoclasts.Unexpectedly,exogenous IL-27p28(~2 ng·mL^(−1) in serum)delivery ameliorated soft tissue abscesses and periimplant bone loss during infection,accompanied by enhanced local IL-27 expression,significant accumulation of RORγt^(+)neutrophils at the infection site,a decrease in RANK^(+) cells,and compromised osteoclast formation.These effects were not observed in IL-27Rα^(−/−)mice compared with WT mice,suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection.In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1,nos2,il17α,il17f,and rorc expression but did not directly stimulate chemotaxis.Collectively,these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S.aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.