Figure 5.

Schematic of immunometabolic changes in macrophages with deletion of Bmal1. Glucose metabolism is increased in macrophages with deletion of Bmal1 which potentiates expression of the pro-inflammatory cytokine IL-1β. In the absence of Bmal1 in macrophages, increased expression of the glucose transporter GLUT1 leads to increased glucose uptake and higher glycolytic pathway activity. Increased dimerization of the glycolytic enzyme PKM2 facilitates its translocation to the nucleus where it phosphorylates STAT3 to drive IL-1β expression. In the mitochondria, flux of pyruvate through pyruvate dehydrogenase (PDH) and oxygen consumption is increased alongside increased Krebs cycle flux which fuels accumulation of the intermediate succinate. Activity of the electron transport chain complex succinate dehydrogenase (SDH) is also increased in Bmal1 ^-/- macrophages which produces heightened levels of ROS which stabilizes HIF-1α to also promote IL-1β expression. Therefore, BMAL1 is regulating glucose metabolism in macrophages to impact upon the expression of IL-1β.