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- Title
Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation.
- Authors
Morita, Yugo; Saito, Motoo; Rangel-Moreno, Javier; Franchini, Anthony M.; Owen, John R.; Martinez, John C.; Daiss, John L.; de Mesy Bentley, Karen L.; Kates, Stephen L.; Schwarz, Edward M.; Muthukrishnan, Gowrishankar
- Abstract
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 IL-27 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 peri-implant 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, il17a, 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.
- Subjects
BONE resorption; BONE cells; CELL physiology; INTRAMUSCULAR injections; ABSCESSES; SURGICAL site; NEUTROPHILS; OSTEOCLASTOGENESIS
- Publication
Bone Research, 2022, Vol 10, Issue 1, p1
- ISSN
2095-4700
- Publication type
Article
- DOI
10.1038/s41413-022-00228-7