Page 44 - Read Online

Page 222 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13

Glucocorticoid levels are strongly related to the activation of the HPA axis, and distinctively affect
macrophage function. Low levels of corticosterone enhanced pro-inflammatory factors, while high
[96]
corticosterone concentrations suppressed macrophage activation . Steroid hormones directly target
mature microglia; glucocorticoids predominantly modulate expression of glucocorticoid receptors to
[97]
regulate microglial inflammatory activity . Anti-inflammatory effect of glucocorticoids on microglia can
reverse the pro-inflammatory function of CRH by attenuating the production of TNF-α, IL-6, and nitric
oxide from LPS + IFN-γ-activated murine microglia. Physical or emotional stress may induce microglial
activation in the brain as determined by changes in morphology [98,99] . The stress-induced elevation of
glucocorticoids can activate microglia in rats, and chronic stress can cause a marked transition from a
[101]
resting to non-resting state [100] . Temporal treatment of glucocorticoids can exhibit the opposite results .
Stress and administration of glucocorticoids prior to peripheral immune stimuli exerted pro-inflammatory
effects on microglia, while exposure to glucocorticoids after stimuli had anti-inflammatory effects in a
rodent model [101] . Corticosteroids limit microglial activation that occurs during acute stress, serving as
an important endogenous suppressive signal limiting neuroinflammation [98,99] . Moreover, glucocorticoid
[88]
level increases and microglial morphological complexity decreases with aging . Increasing glucocorticoid
levels in young mice enhanced microglial ramifications, pointing to their increased neuroprotective
function. The opposite, amoeboid state of microglia renders them to move freely in the brain tissue and is
indicative of inflammatory activation. Amoeboid microglia occur more frequently with aging. The effects
of glucocorticoids or corticosteroids on microglia morphology are dependent on treatment time and
concentration of glucocorticoids.

Estrogen through hypothalamic-pituitary-gonadal axis
The hypothalamic-pituitary-gonadal axis (HPG axis) plays an important role in the reproductive and
immune systems, and controls development, reproduction, and aging in animal models. The hypothalamus
secretes gonadotropin-releasing hormone, the pituitary gland produces luteinizing hormone and follicle-
stimulating hormone, and the gonads release estrogen and testosterone. Although the HPG axis has not
been as deeply studied as the HPA axis, strong evidence suggests that estrogen has the capacity to inhibit
neuroinflammatory processes and can impact immune cells, including microglial functions.

Estradiol (E2) is an estrogen steroid hormone and the major female sex hormone. Studies show
that 17β-estradiol (E2) inhibits microglia activation [102] and reduces the expression of inflammatory
mediators [102] . For example, E2 was able to inhibit Aβ-induced expression of scavenger receptor-A in
microglia cells from an animal model of Alzheimer’s disease [102] . Ovarian hormone deprivation can alter the
expression of major components of estrogen and neuronal inhibitory signaling, participating in the control
of microglia reactivity [103] . Moreover, aging is related to exaggerated responses to acute inflammatory
stimuli, modulated by the duration of hormone deprivation. This deprivation is due to decreased estrogen
[89]
receptor activity, which, despite the continuous synthesis of the receptors, induces neuroinflammation .

SHORT-CHAIN FATTY ACIDS IN THE GUT AND NEUROINFLAMMATION
Microbiota are able to influence brain functions through the production of metabolites such as SCFAs. In
addition to being derived from dietary sources, SCFAs are also produced by the microflora in the distal
small intestine and colon though the fermentation of dietary fibers. The most abundant SCFAs in the
human gut are acetate, propionate, and butyrate. Acetate is used for host synthesis of lipids and cholesterol,
and propionate is mostly absorbed by the liver and serves as a substrate during gluconeogenesis. Butyrate
functions as the main energy source for colonic enterocytes [104] . SCFAs are mainly absorbed in both the
small and large intestine through similar mechanisms, such as diffusion of the dissociated forms and
through active transport by SCFA transporters [105] .

High doses of systemic or locally injected butyrate has been found to exert neuroprotective effects, such
as memory enhancement and cognitive function restoration [106,107] . Physiological levels of butyrate may