THE EFFECTS OF CIRCADIAN RHYTHM ON INFLAMMATORY RESPONSE AND CYTOKINE LEVELS IN HEPATIC MACROPHAGES

Abstract

In mammals, many aspects of daily behavior and physiology such as the sleep-wake cycle, body temperature, and liver metabolism are regulated by endogenous circadian mechanisms. Despite tissue-specific physiological differences, these circadian rhythms share a highly conserved negative feedback mechanism, consisting of transcriptional activators and repressors. This feedback loop system is critical for normal physiology and behavior, and its disruption can lead to sleep disorders, metabolic syndrome, cancer, and a whole host of other diseases, including immune related dysfunction. In this study, the loss of Bmal, a key transcriptional activator, and its ability to regulate a macrophage response was evaluated. To do this, a loxP-cre system was used to create mice with a macrophage-specific deletion of Bmal (lysZ-Bmal -/-). This was the first look at the role of macrophage-specific circadian gene expression in regulation of hepatic immune response and its influence on macrophage differentiation and inflammatory liver disease in vivo. Cre-negative littermate controls and lysZ-Bmal -/- mice were stimulated with the endotoxin lipopolysaccharide (LPS) to provoke a pro-inflammatory response. In lysZ-Bmal -/- mice, cells stimulated with LPS had an exacerbated pro-inflammatory response but a blunted anti-inflammatory response compared to cells from cre-negative littermates. LysZ-Bmal -/- mice also had larger liver to bodyweight ratios as well as increased relative mRNA levels of critical pro-inflammatory cytokines and serum ALT. In summary, this study suggests that circadian regulation in macrophages may be important for lipid control and that Bmal regulates a pro-inflammatory response in hepatic macrophages.