PDF(Pubmed)
Abstract：
BACKGROUND: 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.
RESULTS: 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.
CONCLUSIONS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：先天免疫的年龄相关损伤被认为是金黄色葡萄球菌严重发病的致病因素（S.金黄色葡萄球菌）在骨组织中的感染。然而,金黄色葡萄球菌感染后先天免疫应答的年龄相关性下降的基础仍然知之甚少.
结果：我们来自金黄色葡萄球菌骨髓炎小鼠模型的转录数据（GEO：GSE166522）显示CXCL9和CXCL10（CXCL9/10）上调，本研究在体外和体内进一步证实了这一点。值得注意的是,单核细胞是金黄色葡萄球菌攻击后骨髓产生CXCL9/10的主要来源，但是这种反应在中年小鼠中下降。有趣的是,与年轻小鼠相比，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显着降低。我们进一步表明，单核细胞和巨噬细胞/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，而阻塞轴削弱了这种功能。重要的是,在中年小鼠模型中，用外源性CXCL9或CXCL10治疗可增强，虽然在幼鼠模型中对CXCR3的药理抑制作用减弱，细菌清除和骨髓结构。
结论：这些研究结果表明，在金黄色葡萄球菌感染时，骨髓单核细胞通过CXLCL9/10-CXCR3轴作为先天免疫应答的关键启动子，并且在衰老宿主中对骨骼中金黄色葡萄球菌感染的易感性增加可能主要归因于单核细胞中CXCR9/10的诱导下降。
结果：我们来自金黄色葡萄球菌骨髓炎小鼠模型的转录数据（GEO：GSE166522）显示CXCL9和CXCL10（CXCL9/10）上调，本研究在体外和体内进一步证实了这一点。值得注意的是,单核细胞是金黄色葡萄球菌攻击后骨髓产生CXCL9/10的主要来源，但是这种反应在中年小鼠中下降。有趣的是,与年轻小鼠相比，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显着降低。我们进一步表明，单核细胞和巨噬细胞/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，而阻塞轴削弱了这种功能。重要的是,在中年小鼠模型中，用外源性CXCL9或CXCL10治疗可增强，虽然在幼鼠模型中对CXCR3的药理抑制作用减弱，细菌清除和骨髓结构。
结论：这些研究结果表明，在金黄色葡萄球菌感染时，骨髓单核细胞通过CXLCL9/10-CXCR3轴作为先天免疫应答的关键启动子，并且在衰老宿主中对骨骼中金黄色葡萄球菌感染的易感性增加可能主要归因于单核细胞中CXCR9/10的诱导下降。
