Susceptibility to pathogens in the elderly is heightened with age, largely because of immunosenescence. As an immune regulatory organ, bone marrow creates immune cells that move to other organs and tissues through the blood. Despite the significance of this process of this organ, there is limited research on changes in immune cell generation in the bone marrow and their effects on immunosenescence. In this study, the compositions of immune cells in bone marrow from young (three months) and old (24+ months) mice were compared by means of mass cytometry, with further validation obtained through the reanalysis of single-cell RNA sequencing data and cell sorting via flow cytometry. The effects of differential immune cells on immunosenescence in old mice were evaluated using the Clostridium difficile (C. difficile) infection model. Our results showed that aged mice presented with a reduction in bone trabeculae structure, which was accompanied by a notable increase in polymorphonuclear (PMN)-myeloid-derived suppressor cell (MDSC) abundance. Through bulk-seq and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis, we identified differential genes associated with the immune response—specifically, the Th17 cell differentiation pathway. Furthermore, the increase in exported PMN-MDSCs to the large intestine resulted in increased gut permeability and inflammatory damage to the colon following C. difficile infection. After clearing the PMN-MDSCs in old mice using the anti-Gr-1 antibody, the symptoms induced by C. difficile were significantly relieved, as evidenced by an inhibited IL-17 pathway in the colon and reduced gut permeability. In conclusion, aging increases the number of PMN-MDSCs in both the generated bone marrow and the outputted intestine, which contributes to susceptibility to C. difficile infection. This study provides a novel target for anti-aging therapy for immunosenescence, which is beneficial for improving immune function in elders.

中文翻译：

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PMN-MDSC： 衰老过程中免疫衰老和对艰难梭菌感染易感性增加的罪魁祸首


老年人对病原体的易感性随着年龄的增长而增加，这主要是由于免疫衰老。作为免疫调节器官，骨髓产生免疫细胞，这些免疫细胞通过血液移动到其他器官和组织。尽管该器官的这一过程很重要，但关于骨髓中免疫细胞生成的变化及其对免疫衰老的影响的研究有限。在这项研究中，通过质谱流式细胞术比较了年轻（三个月）和老年（24+ 个月）小鼠骨髓中免疫细胞的组成，并通过流式细胞术对单细胞 RNA 测序数据的重新分析和细胞分选获得进一步的验证。使用艰难梭菌 （C. difficile） 感染模型评估差异免疫细胞对老年小鼠免疫衰老的影响。我们的结果表明，老年小鼠骨小梁结构减少，并伴有多形核 （PMN） -髓源性抑制细胞 （MDSC） 丰度的显着增加。通过批量测序和逆转录定量聚合酶链反应 （RT-qPCR） 分析，我们鉴定了与免疫反应相关的差异基因——特别是 Th17 细胞分化途径。此外，输出到大肠的 PMN-MDSCs 的增加导致艰难梭菌感染后肠道通透性增加和结肠炎症损伤。使用抗 Gr-1 抗体清除老年小鼠体内的 PMN-MDSCs 后，艰难梭菌诱导的症状明显缓解，结肠中 IL-17 通路受抑制和肠道通透性降低证明了这一点。 总之，衰老增加了生成的骨髓和输出的肠道中 PMN-MDSC 的数量，这导致了对艰难梭菌感染的易感性。本研究为免疫衰老的抗衰老治疗提供了新的靶点，有利于改善老年人的免疫功能。