Asquith Mark, Haberthur Kristen, Brown Monica, Engelmann Flora, Murphy Ashleigh, Al-Mahdi Zainab, Messaoudi Ilhem
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA.
Pathobiol Aging Age Relat Dis. 2012;2. doi: 10.3402/pba.v2i0.18052. Epub 2012 Jun 15.
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.
由于免疫功能普遍下降（广义上称为免疫衰老），老年人更容易受到感染。虽然适应性免疫系统中与年龄相关的变化已有充分记录，但固有免疫系统的衰老仍了解较少，尤其是在非人类灵长类动物中。对固有免疫功能中与年龄相关变化的更深入理解，将为老年人感染易感性增加提供机制性见解。恒河猴已被证明是衰老研究的关键转化模型，为剖析固有免疫系统的年龄依赖性调节提供了独特机会。我们研究了以下与年龄相关的变化：（i）固有免疫细胞频率；（ii）模式识别受体（PRR）和固有信号分子的表达；（iii）PRR激动剂刺激后单核细胞和树突状细胞（DC）的细胞因子反应；以及（iv）该模型中的血浆细胞因子水平。我们发现固有免疫细胞的表型和功能都有显著变化。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（TLR4）、成纤维细胞刺激配体-1（TLR2/6）和ODN2006（TLR7/9）在老年mDC中诱导的细胞因子反应降低。有趣的是，除了单核细胞衍生的TNFα对LPS的反应随年龄增加外，TNFα、IL-6和IFNα反应随年龄下降。我们还发现TLR4、TLR5和固有负调节因子含无菌α和TIR基序蛋白（SARM）在幼龄动物中的表达水平均较低。相比之下，黑色素瘤缺失2和视黄酸诱导基因I的表达在老年动物中最低。总之，这些观察结果表明，固有免疫的几个参数受到年龄的显著调节，并导致老年猕猴免疫功能的差异。
