Cytokines and Cognition—The Case for A Head‐to‐Toe Inflammatory Paradigm

Abstract

The brain is not only immunologically active of its own accord, but also has complex peripheral immune interactions. Given the central role of cytokines in neuroimmmunoendocrine processes, it is hypothesized that these molecules influence cognition via diverse mechanisms. Peripheral cytokines penetrate the blood-brain barrier directly via active transport mechanisms or indirectly via vagal nerve stimulation. Peripheral administration of certain cytokines as biological response modifiers produces adverse cognitive effects in animals and humans. There is abundant evidence that inflammatory mechanisms within the central nervous system (CNS) contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Cytokines mediate cellular mechanisms subserving cognition (e.g., cholinergic and dopaminergic pathways) and can modulate neuronal and glial cell function to facilitate neuronal regeneration or neurodegeneration. As such, there is a growing appreciation of the role of cytokine-mediated inflammatory processes in neurodegenerative diseases such as Alzheimer's disease and vascular dementia. Consistent with their involvement as mediators of bidirectional communication between the CNS and the peripheral immune system, cytokines play a key role in the hypothalamic-pituitary-adrenal axis activation seen in stress and depression. In addition, complex cognitive systems such as those that underlie religious beliefs, can modulate the effects of stress on the immune system. Indirect means by which peripheral or central cytokine dysregulation could affect cognition include impaired sleep regulation, micronutrient deficiency induced by appetite suppression, and an array of endocrine interactions. Given the multiple levels at which cytokines are capable of influencing cognition it is plausible that peripheral cytokine dysregulation with advancing age interacts with cognitive aging.

FOXO protects against age‐progressive axonal degeneration

“…Among the potential IRF‐induced genes was FOXO1 itself with predicted IRF3 binding sites within its proximal promoter sequence. This suggests that FOXO1 expression as well as its coregulated genes in the aging brain may be responding to the inflammatory cytokines that are shown to progressively increase with age in the brain (Bodles & Barger, 2004; Wilson, Finch & Cohen, 2002). Indeed, the stimulation of primary neuronal cultures with cytokines shown to increase in aging brains such as interferons (IFN) or tumor necrosis factor (TNF)‐α (Wilson et al., 2002) induced the expression of both FOXO1 and FOXO3 (Fig.…”

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

“…Microglia play a central role in the brain inflammatory response (54)(55)(56) and are affected both by aging and WBI (Figures 3 and 4). Our finding that the basal density of microglia in the SGZ did not change with age is consistent with previous studies of the murine hippocampus (57).…”

“…The decrease in overall microglial density concomitant with the increase in the number of activated microglia after WBI demonstrates a striking pro-inflammatory microenvironment in the SGZ across ages; in old rats approximately 75% of all microglia are activated ( Figure 4E,F). Such chronic brain inflammation has been shown to be deleterious for function in many models of aging-related neurodegenerative diseases (55,56), and may contribute to more severe and prolonged WBI-induced cognitive dysfunction in older animals (29,30). Moreover, although the role of microglia in a proinflammatory response has been investigated more extensively, microglia also serve trophic functions by producing and secreting neurotrophic peptides (61,62).…”

Effect of β-glucan Supplementation on Levels of IgM, IgA, IgG and Its Subclasses IgG1, IgG2, IgG3, and IgG4 in Cancer Patients

“…These problems are most commonly accompanied with mood swings, but might be influenced by additional factors. With well-established central role of cytokines in neuro-immunoendocrine axis one can speculate that these bioactive molecules can affect cognition via several various mechanisms [28,29] . The brain is not Table 1 and Figure 1 summarize immunoglobulin levels.…”

“…The fact that the interaction of cytokines with neurons and glial cells leads to a decrease in cognitive functions is well established (for review see Wilson et al [28] ). The dysregulation of both peripheral and central nervous system cytokine network strongly affects the immune system.…”