Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link

Abstract

Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases. Brain specific or global deficiency of core circadian trans-activator brain and muscle ARNT (Arylhydrocarbon Receptor Nuclear Translocator)-like protein 1 (BMAL1) or that of the transrepressor REV-ERBα, impaired neural function and cognitive performance in rodents. Consistently, transcripts of inflammatory cytokines and host immune responses have been shown to exhibit diurnal variation, in parallel with the disruption of the circadian rhythm. Glucocorticoids that exhibit both a circadian rhythm similar to that of the core clock transactivator BMAL1 and tissue specific ultradian rhythm are critical in the control of neuroinflammation and re-establishment of homeostasis. It is widely accepted that the glucocorticoids suppress nuclear factor-kappa B (NF-κB) mediated transactivation and suppress inflammation. Recent mechanistic elucidations suggest that the core clock components also modulate NF-κB mediated transactivation in the brain and peripheral tissues. In this review we discuss evidence for interactions between the circadian clock components, glucocorticoids and NF-κB signaling responses in the brain and propose glucocorticoid induced leucine zipper (GILZ) encoded by Tsc22d3, as a molecular link that connect all three pathways in the maintenance of CNS homeostasis as well as in the pathogenesis of neuroinflammation-neurodegeneration.

Targeting the blood–brain barrier to delay aging-accompanied neurological diseases by modulating gut microbiota, circadian rhythms, and their interplays

“…Sleep is important for immune regulation at central and peripheral levels and sleep disorders are a risk factor for developing neurodegenerative diseases 110 , and the regulation of sleep by circadian rhythms appear to be vital in maintaining the integrity of BBB 22 . Sleep deprivation (SD) induces a systemic hypo-inflammation characterized by the release of several molecules such as cytokines, chemokines, and acute phase proteins; all of which may promote changes in BBB cellular components, especially in brain endothelial cells 111 .…”

Neuroinflammation and Neurodegenerative Diseases: How Much Do We Still Not Know?

“…Circadian rhythm disorders impact the onset and development of neuroinflammation by activation of glial cells and peripheral immune responses [18,118,119]. Animal models exposed to nightshifts or night light have been confirmed to have significant levels of activated microglia and proinflammatory cytokines in brain [120,121]. Sleep deprivation has also been demonstrated to trigger the transcriptional factor NF-κB and intensify the release of IL-1β and TNF-α in the hippocampus, resulting in neuronal injury [122].…”

“…Inhibition of such cytokines has resulted to reduce spontaneous non-rapid eye movement sleep in experimental animals [124,125], confirming that proinflammatory cytokines induce effects on the circadian cycle and neuroimmune function. In addition, circadian system disorders influence microglial activation and their phenotypes [120][121][122]. Accordingly, under conditions of light exposure, diverse investigations in rats report an increased inflammatory activity of microglia, accompanied by significant rises of TNF-α, IL-1β, and IL-6 [120][121][122]126].…”

“…In addition, circadian system disorders influence microglial activation and their phenotypes [120][121][122]. Accordingly, under conditions of light exposure, diverse investigations in rats report an increased inflammatory activity of microglia, accompanied by significant rises of TNF-α, IL-1β, and IL-6 [120][121][122]126].…”

Natural products for the treatment of depression: Insights into signal pathways influencing the hypothalamic–pituitary–adrenal axis

“…Since the protein encoded by the IκB-α gene acts as an inhibitor of NF-κB, NF-κB remains sequestered in the cytoplasm and cannot translocate into the nucleus to exert its transcriptional function. [ 23 ] Interestingly, NF-κB and glucocorticoid receptors (GR) may interact as functional transcriptional antagonists. Activation of NF-κB is inhibited, leading to increased transcription of GR, thereby reducing elevated GC levels and modulating the overexpression of the HPA axis.…”