(59c) Regulation of Circadian Disruption through Inhibition of NOX2 in Microglia: A Potential Route to Target Neuroinflammation

Sustained neuroinflammation has been shown to be a major contributor to the progression of various neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, among others. Neuroinflammation, like other cellular processes, is affected by the circadian clock. Microglia, the resident immune cells in the brain, act as major contributors to neuroinflammation and are under the influence of the circadian clock. Microglial responses such as activation, recruitment and cytokine expression show rhythmic nature in their response to different stimuli including LPS, Aβ, etc. Mouse models have shown that impairment of the microglial clock results in increased levels of neuroinflammation and worsening of AD disease symptoms. Although the field has grown exponentially in recent decades, there remain significant gaps in our understanding of the complex relationship between circadian rhythms and neuroinflammation. Gaining a mechanistic insight of this intricate relationship will advance the development of interventional therapies that mitigate circadian disruption, thereby preventing neuroinflammation associated with various neurodegenerative diseases. In this study, we focused on a specific, yet under-evaluated, aspect of this complex relationship by examining the interaction between the microglial circadian clock and the enzyme NADPH Oxidase Isoform 2 (NOX2) in BV2 microglial cells. NOX2 activation in microglia results in the production of reactive oxygen species (ROS) leading to increased oxidative stress, an integral characteristic of neuroinflammation. We sought to understand the level of control the microglial circadian clock has on NOX2 expression. We examined the nature of oscillation of the clock gene Per2 and the NOX2 subunits gp91^phoxand p47^phox under distinct types of microglial activation. We also evaluated the impact of NOX2 inhibition on the microglial circadian clock. We discovered that the BV2 microglial clock exerted significant control over NOX2 expression and inhibiting NOX2, in-turn, enabled the microglia to retain a functional circadian clock and reduce levels of ROS and inflammatory cytokines. These findings make NOX2 an attractive therapeutic target to combat circadian disruption and neuroinflammation associated with neurodegenerative diseases.