Circadian dysregulation of immune function in SLE
Circadian rhythm is a universal phenomenon that allows organisms to anticipate and respond to changes in their environment by regulating sleep and feeding patterns, blood pressure, metabolism, detoxification and response to pathogens. Disruption of circadian rhythm contributes to multiple human diseases including cardiovascular diseases, cancer, depression, kidney diseases, metabolic syndrome and inflammation. In previous studies, we found that there is dampening of the renal circadian clock in mouse models of lupus with significant effects on renal physiology including cell metabolism, ion and water transport and blood pressure control. Recent studies have shown that immune function is also tightly regulated by the circadian clock, particularly in monocytes and macrophages. Diurnal variation in inflammatory monocyte release from the bone marrow has a major influence on immune responses to infectious organisms as well as inflammatory responses to tissue damage. Macrophages also have heightened immune surveillance capabilities during the awake hours when exposure to environmental challenges is more likely to occur. Inflammation dampens circadian rhythms leading to a constant state of heightened immune awareness and amplification of the inflammatory state. This new proposal will focus on the role of the monocyte/macrophage circadian clock in mouse models of lupus. Most studies so far have focused on acute infectious and inflammatory conditions that temporarily suppress circadian regulators and there is little known about the effect of chronic inflammatory states on circadian functions in macrophages. Our first aim will address the hypothesis that disruption of the circadian clock in macrophages leads to amplification of inflammatory processes in lupus. We will examine the circadian regulation of peripheral blood monocytes and spleen macrophages and the effect of chronic lupus inflammation on both gene expression patterns and macrophage functions over time during the 24 hour circadian period. Our second aim will address the hypothesis that BMAL1 is a major regulator of macrophage circadian rhythm that protects from inflammation and enhances renal repair. Here we will use mice with macrophage-specific BMAL1 deletion to examine the role of BMAL1 in both spleen and renal macrophages in a lupus model. These studies could lead to new approaches that involve normalization of the macrophage clock so as to help restore immune tolerance.