Disparate Changes in Plasma and Brainstem Cytokine Levels in Adult and Ageing Rats Associated with Age-Related Changes in Facial Motor Neuron Number, Snout Muscle Morphology, and Exploratory Behavior

Abstract

An overall increase in inflammatory cytokines with age in both the blood and the central nervous system (CNS) has been proposed to explain many aspects of ageing, including decreased motor function and neurodegeneration. This study tests the hypothesis that age-related increases in inflammatory cytokines in the blood and CNS lead to facial motor neuron degeneration. Groups of 3–5 female Sprague-Dawley rats aged 3, 12–18, and 24 months were used. Twelve cytokines interleukin (IL)-1α, IL-β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, tumor necrosis factor-α (TNFα), interferon-γ, and granulocyte macrophage-colony stimulating factor were measured in blood plasma and compared with those in the brainstem after first flushing blood from its vessels. The open-field test was used to measure exploratory behavior, and the morphology of the peripheral target muscle of facial motor neurons quantified. Total numbers of facial motor neurons were determined stereologically in separate groups of 3- and 24-month-old rats. Ageing rats showed a significant 30–42% decrease in blood plasma (peripheral) concentrations of IL-12p70 and TNFα and a significant 43–49% increase in brainstem (central) concentrations of IL-1α, IL-2, IL-4, IL-10, and TNFα. They also showed significant reductions in motor neuron number in the right but not left facial nucleus, reduced exploratory behavior, and increase in peripheral target muscle size. Marginal age-related facial motoneuronal loss occurs in the ageing rat and is characterized by complex changes in the inflammatory signature, rather than a general increase in inflammatory cytokines.

Normal aging, motor neurone disease, and Alzheimer’s disease are characterized by cortical changes in inflammatory cytokines

“…We show that normal aging is associated with decreased levels of anti‐inflammatory cytokines, IL‐10 and FGF‐2. The decreased IL‐10 levels found here in the human aging cortex are contrary to what we previously found in aging rat brain stem (Katharesan et al., 2016). However, these results are consistent with studies that report a decline in the production of IL‐10 in cortex of aged mice (Frank et al., 2006; Ye & Johnson, 2001).…”

“…We show that normal aging is associated with decreased levels of anti-inflammatory cytokines, IL-10 and FGF-2. The decreased IL-10 levels found here in the human aging cortex are contrary to what we previously found in aging rat brain stem (Katharesan et al, 2016).…”

“…Of the 27 cytokines, 18 are pro‐inflammatory (IL‐1Ra, IL‐1β, IL‐2, IL‐7, IL‐8, IL‐12, IL‐15, IL‐17A, IFN‐ϒ, TNF‐α, MIP‐1α, MIP‐1β, MCP‐1, IP‐10, regulated on activation, normal T cell expressed and secreted (RANTES), GM‐CSF, VEGF, and eotaxin), eight are anti‐inflammatory (IL‐4, IL‐5, IL‐9, IL‐10, IL‐13, FGF, G‐CSF, and platelet‐derived growth factor bb (PDGF‐bb)), and one (IL‐6) has been shown to have both pro‐inflammatory and anti‐inflammatory effects (Cavaillon, 2001). Our previous studies have reported that facial motoneurons in aging rats were less likely to die following injury compared to young rats (Aperghis et al., 2003) and this correlated with increased levels of IL‐1α, IL‐2, IL‐4, IL‐10, and TNF‐α in the brain stem region where the facial nuclei are located (Katharesan et al., 2016). This raises the possibility that increased levels of certain cytokines with aging may actually be beneficial to motoneurons.…”

Chronic IL-6 overproduction induces a tolerogenic response in aged mice after peripheral nerve injury

“…Although, to our knowledge, the specific effect of IL-6 in microglial phenotype upon a central injury has not been studied, several works proved the relevance of cytokine environment related to injury outcome during aging. For instance, a study showed that levels of cytokines upon LPS administration (consisting of IL-1α, IL-2, IL-4, IL-10, and TNF-α) in the brainstem of young rats closely mimicked those of aged rats in basal conditions (Katharesan et al 2016), and that LPS administered in adult rats before facial nerve avulsion reduced FMN death (Katharesan et al 2018). In view of our results and the current literature, it may be interesting to deepen in the effect of the cytokine environment in the modulation of the IL-6 effect during aging.…”