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.

Interleukin-27 是一种多效细胞因子，其在细菌感染期间的功能仍存在争议，并且其在金黄色葡萄球菌骨髓炎患者中的作用尚不清楚。为了解决这一知识差距，我们完成了一项临床研究，观察到与健康对照相比，患者血清 IL-27 水平升高（高 20 倍， P < 0.05）。值得注意的是，脓毒症死亡后患者的 IL-27 血清水平比未感染患者高 60 倍（ P < 0.05），表明 IL-27 具有致病作用。为了检验这一假设，我们分别通过肌内注射 rAAV-IL-27p28 或 rAAV-GFP 评估了 WT 和 IL-27Rα ^-/−小鼠中有或没有外源性 IL-27 诱导的金黄色葡萄球菌骨髓炎。我们发现，在骨金黄色葡萄球菌感染后 1 天内，IL-27 在手术部位被诱导，并由 M0、M1 和 M2 巨噬细胞和成骨细胞表达，但破骨细胞不表达。出乎意料的是，外源性IL-27p28（血清中~2 ng·mL ^-1 ）的递送改善了感染期间的软组织脓肿和种植体周围骨丢失，同时局部IL-27表达增强，感染部位RORγt ⁺中性粒细胞显着积聚，RANK ⁺细胞减少，破骨细胞形成受损。与 WT 小鼠相比，IL-27Rα ^-/−小鼠中没有观察到这些效应，这表明 IL-27 对于免疫来说是可有可无的，但在感染过程中介导了多余的免疫和骨细胞功能。受感染胫骨的体外研究和批量 RNA 测序表明，IL-27 增加了nos1、nos2 、 il17a 、 il17f和rorc表达，但不直接刺激趋化性。 总的来说，这些结果发现了金黄色葡萄球菌感染骨后成骨细胞立即表达 IL-27 的新现象，并表明全身性 IL-27 在骨髓炎中具有保护作用。