Microglia inflammatory responses are controlled by an intrinsic circadian clock

Abstract

The circadian system regulates many physiological functions including inflammatory responses. For example, mortality caused by lipopolysaccharide (LPS) injection varies depending on the time of immunostimulation in mammals. The effects of more subtle challenges on the immune system and cellular mechanisms underlying circadian differences in neuroinflammatory responses are not well understood. Here we show that adult male Sprague-Dawley rats injected with a sub-septic dose of LPS during the light phase displayed elevated sickness behaviors and hippocampal cytokine production compared to rats injected during the dark phase. Microglia are the primary central nervous system (CNS) immune cell type and may mediate diurnal differences in sickness response, thus we explored whether microglia demonstrate temporal variations in inflammatory factors. Hippocampal microglia isolated from adult rats rhythmically expressed inflammatory factors and circadian clock genes. Microglia displayed robust rhythms of TNFα, IL1β and IL6 mRNA, with peak cytokine gene expression occurring during the middle of the light phase. Microglia isolated during the light phase were also more reactive to immune stimulation; such that, ex vivo LPS treatment induced an exaggerated cytokine response in light phase-isolated microglia. Treating microglia with corticosterone ex vivo induced expression of the circadian clock gene Per1. However, microglia isolated from adrenalectomized rats maintained temporal differences in clock and inflammatory gene expression. This suggests circadian clock gene expression in microglia is entrained by, but oscillates in the absence of, glucocorticoids. Taken together, these findings demonstrate that microglia possess a circadian clock that influences inflammatory responses. These results indicate time-of-day is an important factor to consider when planning inflammatory interventions such as surgeries or immunotherapies.

Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis

“…At the molecular level, the clock is comprised of at least three interlocking transcription loops, which regulate circadian oscillations in gene expression within the cell (1). In the immune system, intrinsic clocks have been identified in various cell lineages, including macrophages, lymphocytes, and microglia (1)(2)(3). Direct control of immune gene expression, among them proinflammatory cytokines, by the clock transcription factors BMAL and REV-ERBα also has been demonstrated (4-7).…”

“…Monocytes are bone marrow-derived cells characterized by Ly6c hi / CCR2 hi expression, which are recruited to the sites of infection and injury, including those occurring in the CNS (2,3,13,14). These cells have the capacity to differentiate into macrophages and dendritic cells (DC), perform effector functions such as antigen presentation and T-cell stimulation, and produce proinflammatory cytokines and chemokines, all directed to contain and clear infection (8,9,13,15).…”

Endocrine Effects of Circadian Disruption

“…Diurnal rhythms in melatonin and glucocorticoids can directly affect immune responses through their potent anti-inflammatory actions (110,111). However, these hormones also indirectly affect the immune system via their entraining properties on peripheral cells (106,112). Exposure to light at night and to non-24-h light cycles alters inflammatory responses in the peripheral and central nervous systems (113)(114)(115).…”

“…Inflammatory challenges can result in vastly different outcomes depending on the time at which they occur. For example, sickness behavior and cytokine production vary depending on the time of endotoxic challenge in both humans and rodents (105)(106)(107). Furthermore, several inflammatory diseases, including asthma and rheumatoid arthritis, fluctuate in severity over the course of the day, implicating circadian regulation of inflammatory processes (108,109).…”

A New Perspective for Parkinson’s Disease: Circadian Rhythm

“…First, it is certain that circadian disruption could exacerbate some pathological events of PD. For example, neuroinflammation is controlled by the intrinsic circadian clock in the microglia [117], and Bmal -/-could induce robust neuroinflammation responses. The amount of autophagy-related proteins in the brain displayed a 24 h rhythm, which could be blunted by sleep fragmentation [118].…”