Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838 North of Guangzhou Avenue, Guangzhou, Guangdong Province, 510515, China.
Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China.
Cell Mol Life Sci. 2024 Jul 13;81(1):300. doi: 10.1007/s00018-024-05311-2.
Age-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood.
Our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure.
These findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.
人们认为，与年龄相关的固有免疫损伤是导致金黄色葡萄球菌（S. aureus）感染骨骼组织时严重发病机制的一个致病因素。然而，S. aureus 感染时固有免疫反应随年龄下降的基础仍知之甚少。
我们从金黄色葡萄球菌骨髓炎的小鼠模型中获得的转录数据（GEO：GSE166522）显示 CXCL9 和 CXCL10（CXCL9/10）上调，本研究进一步在体外和体内得到证实。值得注意的是，单核细胞是金黄色葡萄球菌攻击时骨髓中 CXCL9/10 产生的主要来源，但这种反应在中年小鼠中下降。有趣的是，从中年小鼠骨髓单核细胞的条件培养基对中性粒细胞和巨噬细胞的杀菌功能的影响明显低于年轻小鼠。我们进一步表明，单核细胞与巨噬细胞/中性粒细胞之间的 CXCL9/10-CXCR3 轴的激活促进了细胞的杀菌功能，而阻断该轴则损害了这种功能。重要的是，在中年小鼠模型中使用外源性 CXCL9 或 CXCL10 治疗可增强，而在年轻小鼠模型中抑制 CXCR3 的药理作用则会损害细菌清除和骨髓结构。
这些发现表明，骨髓单核细胞通过金黄色葡萄球菌感染时的 CXCLCL9/10-CXCR3 轴作为固有免疫反应的关键促进剂发挥作用，而在老年宿主中骨骼对金黄色葡萄球菌感染的易感性增加可能在很大程度上归因于单核细胞中 CXCR9/10 的诱导下降。
