Abstract
Microglia are the immune cells of the brain. Hyperactivation of microglia contributes to the pathology of metabolic and neuroinflammatory diseases. Evidence has emerged that links the circadian clock, cellular metabolism, and immune activity in microglia. Rev-erb nuclear receptors are known for their regulatory role in both the molecular clock and cell metabolism, and have recently been found to play an important role in neuroinflammation. The Rev-erbα agonist SR9011 disrupts circadian rhythm by altering intracellular clock machinery. However, the exact role of Rev-erbα in microglial immunometabolism remains to be elucidated. In the current study, we explored whether SR9011 also had such a detrimental impact on microglial immunometabolic functions. Primary microglia were isolated from 1–3 days old Sprague-Dawley rat pups. The expression of clock genes, cytokines and metabolic genes was evaluated using RT-PCR and rhythmic expression was analyzed. Phagocytic activity was determined by the uptake capacity of fluorescent microspheres. Mitochondria function was evaluated by measuring oxygen consumption rate and extracellular acidification rate. We found that key cytokines and metabolic genes are rhythmically expressed in microglia. SR9011 disturbed rhythmic expression of clock genes in microglia. Pro-inflammatory cytokine expression was attenuated by SR9011 during an immune challenge by TNFα, while expression of the anti-inflammatory cytokine Il10 was stimulated. Moreover, SR9011 decreased phagocytic activity, mitochondrial respiration, ATP production, and metabolic gene expression. Our study highlights the link between the intrinsic clock and immunometabolism of microglia. We show that Rev-erbα is implicated in both metabolic homeostasis and the inflammatory responses in microglia, which has important implications for the treatment of metabolic and neuroinflammatory diseases.
Highlights
The circadian brain clock orchestrates physiological and metabolic processes to prepare the body for environmental changes and to optimize energy metabolism [1]
To confirm whether cytokines and metabolic genes were temporally regulated in primary microglia, we investigated the expression of three key proinflammatory cytokines – interleukin-1 beta (Il1β), interleukin-6 (Il6), and tumor necrosis factor-alpha (Tnf α), as well as three important metabolic genes – carnitine palmitoyltransferase 1 (Cpt1), hexokinase 2 (Hk2), and pyruvate dehydrogenase kinase 1 (Pdk1)
SR9011 in combination with dexamethasone had no impact on cell viability (Figure 2G), indicating that a decrease in gene expression could not be attributed to cell death. These results show that SR9011 disrupted the rhythm of clock gene expression, pertaining to both amplitude and phase depending on the clock gene, which means that rhythmic expression of clock gene expression became nonrhythmic after adding SR9011
Summary
The circadian brain clock orchestrates physiological and metabolic processes to prepare the body for environmental changes and to optimize energy metabolism [1]. The nuclear receptor reverse viral erythroblastosis oncogene product alpha (Rev-erbα) plays a crucial role in both the molecular clock of the circadian timing system and the regulation of metabolism. Systemic administration of the Rev-erbα agonist SR9011 altered clock genes expression and disrupted the circadian behavior of mice leading to loss of locomotor activity during the active phase (dark phase), while vehicle administration caused no disruption [23]. These results show that Rev-erb nuclear receptors have profound effects on circadian rhythm, metabolism and neuroinflammation, and possibly are eligible targets for treating metabolic diseases
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