Hofstee Marloes I, Heider Anja, Häckel Sonja, Constant Caroline, Riool Martijn, Richards R Geoff, Moriarty T Fintan, Zaat Sebastian A J
AO Research Institute Davos, 7270 Davos, Switzerland.
Department of Medical Microbiology and Infection Prevention, Amsterdam UMC, Amsterdam Institute for Infection and Immunity, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Pathogens. 2021 Nov 6;10(11):1446. doi: 10.3390/pathogens10111446.
is the main causative pathogen of subcutaneous, bone, and implant-related infections, forming structures known as staphylococcal abscess communities (SACs) within tissues that also contain immunosuppressive myeloid-derived suppressor cells (MDSCs). Although both SACs and MDSCs are present in chronic infections, it remains unknown whether SACs directly trigger MDSC expansion. To investigate this, a previously developed 3D in vitro SAC model was co-cultured with murine and human bone marrow cells. Subsequently, it was shown that SAC-exposed human CD11b myeloid cells or SAC-exposed murine CD11b Gr-1 cells were immunosuppressive mainly by reducing absolute CD4 and CD8α T cell numbers, as shown in T cell proliferation assays and with flow cytometry. Monocytic MDSCs from mice with an bone infection also strongly reduced CD4 and CD8α T cell numbers. Using protein biomarker analysis and an immunoassay, we detected in SAC-bone marrow co-cultures high levels of GM-CSF, IL-6, VEGF, IL-1β, TNFα, IL-10, and TGF-β. Furthermore, SAC-exposed neutrophils expressed Arg-1 and SAC-exposed monocytes expressed Arg-1 and iNOS, as shown via immunofluorescent stains. Overall, this study showed that SACs cause MDSC expansion from bone marrow cells and identified possible mediators to target as an additional strategy for treating chronic infections.
是皮下、骨骼及植入物相关感染的主要致病病原体，可在组织内形成称为葡萄球菌脓肿群落（SACs）的结构，这些组织中还含有免疫抑制性骨髓来源的抑制细胞（MDSCs）。尽管SACs和MDSCs都存在于慢性感染中，但SACs是否直接触发MDSC扩增仍不清楚。为了研究这一点，将先前开发的3D体外SAC模型与小鼠和人类骨髓细胞共培养。随后发现，如在T细胞增殖试验和流式细胞术中所示，暴露于SAC的人类CD11b髓样细胞或暴露于SAC的小鼠CD11b Gr-1细胞主要通过减少绝对CD4和CD8α T细胞数量而具有免疫抑制作用。患有骨感染的小鼠的单核细胞MDSCs也强烈减少了CD4和CD8α T细胞数量。通过蛋白质生物标志物分析和免疫测定，我们在SAC-骨髓共培养物中检测到高水平的GM-CSF、IL-6、VEGF、IL-1β、TNFα、IL-10和TGF-β。此外，如通过免疫荧光染色所示，暴露于SAC的中性粒细胞表达精氨酸酶1（Arg-1），暴露于SAC的单核细胞表达Arg-1和诱导型一氧化氮合酶（iNOS）。总体而言，这项研究表明SACs可导致骨髓细胞的MDSC扩增，并确定了可能作为治疗慢性感染的额外策略的靶向介质。
