Circadian Clock Regulates Inflammation and the Development of Neurodegeneration

Abstract

The circadian clock regulates numerous key physiological processes and maintains cellular, tissue, and systemic homeostasis. Disruption of circadian clock machinery influences key activities involved in immune response and brain function. Moreover, Immune activation has been closely linked to neurodegeneration. Here, we review the molecular clock machinery and the diurnal variation of immune activity. We summarize the circadian control of immunity in both central and peripheral immune cells, as well as the circadian regulation of brain cells that are implicated in neurodegeneration. We explore the important role of systemic inflammation on neurodegeneration. The circadian clock modulates cellular metabolism, which could be a mechanism underlying circadian control. We also discuss the circadian interventions implicated in inflammation and neurodegeneration. Targeting circadian clocks could be a potential strategy for the prevention and treatment of inflammation and neurodegenerative diseases.

Keywords: cellular metabolism; circadian clock; immune response; neurodegeneration; systemic inflammation.

Figure 1

The circadian clock machinery in mammals. The mammalian circadian clock network at the molecular level consists of transcription-translation feedback loops (TTFLs). Bmal1/Clock heterodimer activates the transcription of genes that containing E-box elements in their promoters, such as Per1/2/3, Cry1/2, Rorα, Rev-erbα, and Dbp. Per and Cry proteins translocate back into the nucleus and repress the activity of the Bmal1/Clock complex, which subsequently inhibits their own expression. Rorα and Rev-erbα fine-tune the expression of Bmal1 and Nfil3, via activation and repression, respectively. DBP and NFIL3 regulate the expression of Per. Besides, the stability and nuclear translocation of circadian clock proteins are modulated by post-translational modifications (PTMs). Circadian clocks also control the rhythmic expression of numerous clock-controlled genes (CCGs) and biological processes, such as immunity and brain function.

Figure 2

The circadian clock regulates immune function and neurodegeneration. Disruption of the circadian clock machinery leads to immune dysfunction and neurodegeneration, which, in turn, exacerbates the circadian abnormality. The bidirectional communication between systemic inflammation and neurodegeneration deteriorates immune dysfunction and the progression of neurodegenerative diseases. The cellular metabolism pathway could be a mechanism underlying circadian control of immunity and brain function.