Department of Morphological and Biomedical Sciences, Faculty of Medicine, University of Verona, 37134 Verona, Italy.
Brain Behav Immun. 2010 Jan;24(1):138-52. doi: 10.1016/j.bbi.2009.09.006. Epub 2009 Sep 16.
Aging is often accompanied by increased levels of inflammatory molecules in the organism, but age-related changes in the brain response to inflammatory challenges still require clarification. We here investigated in mice whether cytokine signaling and T-cell neuroinvasion undergo age-related changes. We first analyzed the expression of molecules involved in T-cell infiltration and cytokine signaling regulation in the septum and hippocampus of 2-3 months and 20- to 24-month-old mice at 4h after intracerebroventricular injections of tumor necrosis factor (TNF)-alpha or interferon-gammaversus saline injections. Transcripts of the chemokine CXCL9, intercellular adhesion molecule (ICAM)-1 and suppressor of cytokine signaling molecules (SOCS) 1 and 3 were increased in both age groups after cytokine injection; microglia-derived matrix metalloproteinase (MMP) 12 mRNA was induced in old mice also after control saline injections. Age-related changes in ICAM-1 protein expression and T-cell infiltration were then analyzed in mice of 3-4, 8-9 and 15-16 months at 48h after TNF-alpha injections. ICAM-1 immunoreactivity, and Western blotting in striatum, septum, hippocampus and hypothalamus showed progressive age-related enhancement of TNF-alpha-elicited ICAM-1 upregulation. Double immunofluorescence revealed ICAM-1 expression in microglia and astrocytic processes. CD3(+), CD4(+) and CD8(+) T-cells exhibited progressive age-related increases in brain parenchyma and choroid plexus after cytokine exposure. The findings indicate that the brain responses to inflammatory challenges are not only preserved with advancing age, but also include gradual amplification of ICAM-1 expression and T-cell recruitment. The data highlight molecular and cellular correlates of age-related increase of brain sensitivity to inflammatory stimuli, which could be involved in altered brain vulnerability during aging.
衰老通常伴随着机体中炎症分子水平的升高，但与年龄相关的大脑对炎症挑战的反应变化仍需阐明。我们在这里研究了小鼠中细胞因子信号传导和 T 细胞神经入侵是否会发生与年龄相关的变化。我们首先分析了在 TNF-α或干扰素-γ脑室内注射后 4 小时，2-3 个月和 20-24 个月大的小鼠隔室和海马中涉及 T 细胞浸润和细胞因子信号传导调节的分子的表达，与生理盐水注射相比。趋化因子 CXCL9、细胞间黏附分子（ICAM）-1 和细胞因子信号转导抑制物（SOCS）1 和 3 的转录物在两个年龄组中均在细胞因子注射后增加；老年小鼠在对照生理盐水注射后也诱导了小胶质细胞衍生的基质金属蛋白酶（MMP）12 mRNA。然后在 TNF-α注射后 48 小时，分析了 3-4、8-9 和 15-16 个月大的小鼠中 ICAM-1 蛋白表达和 T 细胞浸润的年龄相关性变化。ICAM-1 免疫反应性和纹状体、隔室、海马和下丘脑的 Western blot 显示 TNF-α引发的 ICAM-1 上调逐渐随年龄相关增强。双重免疫荧光显示 ICAM-1 在小胶质细胞和星形胶质细胞突起中表达。CD3（+），CD4（+）和 CD8（+）T 细胞在细胞因子暴露后在脑实质和脉络丛中逐渐随年龄相关增加。这些发现表明，大脑对炎症挑战的反应不仅随着年龄的增长而保留，而且还包括 ICAM-1 表达和 T 细胞募集的逐渐放大。这些数据突出了与年龄相关的大脑对炎症刺激敏感性增加的分子和细胞相关性，这可能与衰老过程中大脑易损性的改变有关。
