Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta).
Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta).
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DOI：
10.3402/pba.v2i0.18052
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Messaoudi I
中科院分区：
文献类型：
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作者：
Asquith M;Haberthur K;Brown M;Engelmann F;Murphy A;Al-Mahdi Z;Messaoudi I
老年人更容易受到感染，因为免疫功能普遍下降，广泛称为免疫衰老。虽然适应性免疫系统中与年龄相关的变化有很好的记录，但先天免疫系统的衰老仍然不太清楚，特别是在非人灵长类动物中。对先天免疫功能中与年龄相关的变化的更有力的理解将为老年人对感染的易感性增加提供机制性的见解。恒河猴已被证明是衰老研究的关键转化模型，并为解剖先天免疫系统的年龄依赖性调节提供了独特的机会。我们检查了年龄相关的变化：（i）先天免疫细胞频率;（ii）模式识别受体（PRR）和先天信号分子的表达;（iii）用PRR激动剂刺激后单核细胞和树突状细胞（DC）的细胞因子应答;以及（iv）该模型中的血浆细胞因子水平。我们发现先天免疫细胞的表型和功能都发生了显著变化。这包括与年龄相关的髓样DC（mDC）频率增加。此外，我们发现toll样受体（TLR）激动剂脂多糖（TLR 4）、成纤维细胞刺激配体-1（TLR 2/6）和ODN 2006（TLR 7/9）在老化的mDC中诱导降低的细胞因子应答。有趣的是，除了单核细胞源性TNFα对LPS的反应随年龄增加而增加外，TNFα、IL-6和IFNα的反应随年龄下降。我们还发现TLR 4、TLR 5和先天性负调节因子，不育α和含TIR基序的蛋白（SARM），在年轻动物中的表达水平都较低。相比之下，黑色素瘤2和视黄酸诱导基因I的表达是最低的老年动物。总之，这些观察结果表明，先天免疫的几个参数显着调制的年龄，并有助于老年猕猴的免疫功能差异。
Aged individuals are more susceptible to infections due to a general decline in immune function broadly referred to as immune senescence. While age-related changes in the adaptive immune system are well documented, aging of the innate immune system remains less well understood, particularly in nonhuman primates. A more robust understanding of age-related changes in innate immune function would provide mechanistic insight into the increased susceptibility of the elderly to infection. Rhesus macaques have proved a critical translational model for aging research, and present a unique opportunity to dissect age-dependent modulation of the innate immune system. We examined age-related changes in: (i) innate immune cell frequencies; (ii) expression of pattern recognition receptors (PRRs) and innate signaling molecules; (iii) cytokine responses of monocytes and dendritic cells (DC) following stimulation with PRR agonists; and (iv) plasma cytokine levels in this model. We found marked changes in both the phenotype and function of innate immune cells. This included an age-associated increased frequency of myeloid DC (mDC). Moreover, we found toll-like receptor (TLR) agonists lipopolysaccharide (TLR4), fibroblast stimulating ligand-1 (TLR2/6), and ODN2006 (TLR7/9) induced reduced cytokine responses in aged mDC. Interestingly, with the exception of the monocyte-derived TNFα response to LPS, which increased with age, TNFα, IL-6, and IFNα responses declined with age. We also found that TLR4, TLR5, and innate negative regulator, sterile alpha and TIR motif containing protein (SARM), were all expressed at lower levels in young animals. By contrast, absent in melanoma 2 and retinoic acid-inducible gene I expression was lowest in aged animals. Together, these observations indicate that several parameters of innate immunity are significantly modulated by age and contribute to differential immune function in aged macaques.