Biphasic effects of IL-27 during Staphylococcus aureus implant-associated osteomyelitis in mice
Interleukin-27 is a pleiotropic cytokine whose reported functions during bacterial infections are debated as an area of active research. To address this, we investigated the role of IL-27 signaling during Staphylococcus aureus osteomyelitis. Clinically, we observed elevated serum IL-27 levels (20-fold higher, p<0.05) in patients with S. aureus osteomyelitis compared to uninfected patients undergoing elective total joint replacement. Remarkably, IL-27 serum levels immediately following septic death were 60-fold higher vs. uninfected patients (p<0.05), suggesting that IL-27 may be a biomarker of end-stage infection and/or cytokine storm. To test this, we hypothesized that IL-27 mediates bacterial clearance during the acute phase of S. aureus osteomyelitis, and subsequently suppresses inflammation to prevent cytokine storm and osteolysis during chronic infection. In mice, we observed that systemic IL-27 delivery by a recombinant adeno-associated viral vector (rAAV-IL-27) ameliorates surgical site soft tissue infection and peri-implant bone loss during the establishment of implant-associated S. aureus osteomyelitis. This effect was not observed in IL-27 receptor knock-out mice, suggesting a direct role of IL-27/IL-27R signaling on immune and bone cell functions. Examination of IL-27-mediated immune responses via transcriptome analyses of infected tibiae demonstrated that IL-27 is a biphasic cytokine with IL-27/IL-27R activating immunostimulatory responses including Th17, IL-2, TLR, and iNOS signaling early, and subsequently suppressing these pathways during chronic infection. Ex vivo confirmation using murine macrophages revealed that IL-27 co-stimulates TLR signaling to increase the production of nitric oxide, and immunomodulatory cytokines such as IL-10, IL-21, IL-31, and TNF-{beta}, but is not a chemokine. Author SummaryStaphylococcus aureus is the most common pathogen in orthopaedic infections, and hard-to-treat (MRSA) strains cause >50% of these infections. Thus, there is an urgent need to develop immunotherapies to treat these life-threatening S. aureus infections. Currently, the role of multifunctional IL-27 on S. aureus osteomyelitis is unknown. In a clinical study, we observed that IL-27 is an important biomarker for identifying S. aureus osteomyelitis patients, and that elevated serum IL-27 levels correlated with adverse clinical outcomes, such as septic death. In our efforts to uncover the underlying mechanisms, we reveal that IL-27 is a biphasic cytokine, activating proinflammatory immune pathways, including Th17 responses, early during acute S. aureus osteomyelitis, and subsequently repressing them during the chronic phase to prevent cytokine storm and bone damage. These results indicate that immune modulation of IL-27/IL-27R signaling could be a viable therapeutic strategy in mitigating S. aureus osteomyelitis.