Regulation of Cytokine Signaling and T-cell Recruitment in the Aging Mouse Brain in Response to Central Inflammatory Challenge

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.