Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI), resulting in considerable disability and prolonged treatment. It is known that host leukocyte IL-10 production is required for S. aureus biofilm persistence in PJI. An S. aureus bursa aurealis Tn library consisting of 1,952 non-essential genes was screened for mutants that failed to induce IL-10 in myeloid-derived suppressor cells (MDSCs), which identified a critical role for bacterial lactic acid biosynthesis. We generated an S. aureus ddh/ldh1/ldh2 triple Tn mutant that cannot produce d- or l-lactate. Co-culture of MDSCs or macrophages with ddh/ldh1/ldh2 mutant biofilm produced substantially less IL-10 compared with wild-type S. aureus, which was also observed in a mouse model of PJI and led to reduced biofilm burden. Using MDSCs recovered from the mouse PJI model and in vitro leukocyte–biofilm co-cultures, we show that bacterial-derived lactate inhibits histone deacetylase 11, causing unchecked HDAC6 activity and increased histone 3 acetylation at the Il-10 promoter, resulting in enhanced Il-10 transcription in MDSCs and macrophages. Finally, we show that synovial fluid of patients with PJI contains elevated amounts of d-lactate and IL-10 compared with control subjects, and bacterial lactate increases IL-10 production by human monocyte-derived macrophages.

金黄色葡萄球菌是与生物膜相关的人工关节感染（PJI）的主要原因，导致严重的残疾和长期的治疗。已知在PJI中金黄色葡萄球菌生物膜持续存在需要宿主白细胞IL-10的产生。的金黄色葡萄球菌囊aurealis Tn的组成的1952非必需基因文库进行筛选对于未能诱导IL-10在髓源抑制细胞（MDSC的），它确定了细菌乳酸的生物合成中起关键作用的突变体。我们产生了不能产生d-或l-乳酸的金黄色葡萄球菌ddh / ldh1 / ldh2三重Tn突变体。MDSC或巨噬细胞与ddh / ldh1 / ldh2的共培养与野生型金黄色葡萄球菌相比，突变型生物膜产生的IL-10少得多，这在PJI小鼠模型中也观察到，并导致生物膜负担减少。使用从小鼠PJI模型和体外白细胞-生物膜共培养物中回收的MDSC，我们显示细菌来源的乳酸抑制组蛋白脱乙酰基酶11，导致未经检查的HDAC6活性，并在Il-10启动子处增加组蛋白3乙酰化，导致增强的Il MDSC和巨噬细胞中的-10转录。最后，我们显示与对照对象相比，PJI患者的滑液含有升高的d-乳酸和IL-10量，细菌乳酸会增加人单核细胞衍生的巨噬细胞产生IL-10。