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Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism
Xiao-Lan Wang1,2,3, Samantha E C Wolff2,3, Nikita Korpel2,3,4
1Université de Strasbourg, Laboratoire de Neuroscience Cognitives et Adaptatives (LNCA), Strasbourg, France.
Abstract:
Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 (Bmal1) plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. Bmal1 deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in Bmal1 knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that Bmal1 is a key regulator in microglial immune response and cellular metabolism.
Insights
The circadian clock influences brain immune cell function. The core clock gene Brain and Muscle Arnt-like 1 (Bmal1) regulates microglial immune responses and metabolism, impacting neuroinflammation and cellular health.
Area of Science:
- Neuroimmunology
- Chronobiology
- Cellular Metabolism
Background:
- Microglia, the brain's immune cells, are crucial for surveillance but implicated in neuroinflammation and neurodegeneration.
- Microglial immune responses must adapt to various stressors.
- The circadian clock regulates inflammation and energy balance.
Purpose of the Study:
- To investigate the role of circadian variation in microglial immune responses.
- To determine the function of the core clock gene Brain and Muscle Arnt-like 1 (Bmal1) in microglial immune regulation and metabolism.
Main Methods:
- Isolation of microglial cells from mice and culture of BV-2 microglial cells.
- Quantitative RT-PCR to analyze gene expression.
- Experimental manipulation of Bmal1 expression (deficiency and knockdown) under inflammatory (LPS) and metabolic (palmitic acid) stress.
Main Results:
- Significant circadian variation in microglial markers for inflammation, nutrient utilization, and antioxidation was observed.
- Bmal1 deficiency altered microglial gene expression, decreasing pro-inflammatory cytokines and increasing antioxidative/anti-inflammatory factors.
- Bmal1 deficiency impacted metabolic gene expression, enhanced metabolic processes, and increased microglial phagocytic capacity.
Conclusions:
- Bmal1 is a critical regulator of microglial immune function.
- Bmal1 plays a significant role in modulating microglial cellular metabolism.
- Circadian regulation by Bmal1 is essential for appropriate microglial responses to stressors.
