Prakash Sangeetha, Agrawal Sudhanshu, Cao Jia-ning, Gupta Sudhir, Agrawal Anshu
Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, CA, 92697, USA.
Age (Dordr). 2013 Oct;35(5):1785-97. doi: 10.1007/s11357-012-9477-8. Epub 2012 Sep 25.
Increased susceptibility to respiratory infections such as influenza is the hallmark of advancing age. The mechanisms underlying the impaired immune response to influenza are not well understood. In the present study, we have investigated the effect of advancing age on dendritic cell (DC) function because they are critical in generating robust antiviral responses. Our results indicate that monocyte derived DCs from the aged are impaired in their capacity to secrete interferon (IFN)-I in response to influenza virus. Additionally, we observed a severe reduction in the production of IFN-III, which plays an important role in defense against viral infections at respiratory mucosal surfaces. This reduction in IFN-I and IFN-III were a result of age-associated modifications in the chromatin structure. Investigations using chromatin immunoprecipitation with H3K4me3 and H3K9me3 antibodies revealed that there is increased association of IFN-I and IFN-III promoters with the repressor histone, H3K9me3 in non-stimulated aged DCs compared to young DCs. This was accompanied by decreased association of these promoters with activator histone, H3K4me3 in aged DCs after activation with influenza. In contrast to interferons, the association of TNF-alpha promoter with both these histones was comparable between aged and young subjects. Investigations at 48 h suggested that these changes are not stable and change with time. In summary, our study demonstrates that myeloid DCs from aged subjects are impaired in their capacity to produce IFNs in response to influenza virus and that age-associated altered histone expression patterns are responsible for the decrease in IFN production.
对流感等呼吸道感染易感性增加是衰老的标志。对流感免疫反应受损的潜在机制尚未完全了解。在本研究中，我们研究了衰老对树突状细胞（DC）功能的影响，因为它们在产生强大的抗病毒反应中起关键作用。我们的结果表明，来自老年人的单核细胞衍生DC在对流感病毒作出反应时分泌I型干扰素（IFN）的能力受损。此外，我们观察到III型干扰素的产生严重减少，III型干扰素在呼吸道粘膜表面抵御病毒感染中起重要作用。I型干扰素和III型干扰素的这种减少是染色质结构中与年龄相关的修饰的结果。使用H3K4me3和H3K9me3抗体进行的染色质免疫沉淀研究表明，与年轻DC相比，未刺激的老年DC中I型干扰素和III型干扰素启动子与抑制性组蛋白H3K9me3的结合增加。在用流感激活后，老年DC中这些启动子与激活剂组蛋白H3K4me3的结合减少。与干扰素不同，老年和年轻受试者中TNF-α启动子与这两种组蛋白的结合相当。48小时的研究表明，这些变化不稳定且随时间变化。总之，我们的研究表明，老年受试者的髓样DC在对流感病毒作出反应时产生干扰素的能力受损，并且与年龄相关的组蛋白表达模式改变是干扰素产生减少的原因。
