UC San Diego

Macrophages, a.k.a ‘big eaters’ are key cells in our immune system. These effector cells of the innate immune system phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages also play a pivotal role in eliminating diseased and damaged cells. Macrophages have a strong intrinsic circadian rhythm that regulates the diurnal rhythmicity of their immune responses, including immunosurveillance, infiltration to sites of injury, pathogen recognition, pathogen clearance, and the timely resolution of inflammation. A healthy macrophage circadian rhythm is crucial for appropriate defensive responses and is completely lost during the immunosenescence chapter of life one experiences on aging. Here we have stumbled upon a novel regulator of the macrophage circadian rhythm, GIV/Girdin, a multi-modular G protein activator and a potent inhibitor of cAMP. Using publicly available datasets, we show that GIV expression undergoes rhythmic cycling that is lost in aged mice. GIV depleted Raw 264.7 macrophages show significant variation in the expression of their peripheral clock genes. We also demonstrated that peritoneal macrophages display significant diurnal variation in their expression of Cry1 and Klf-4, two genes crucial for a healthy macrophage circadian rhythm and time-of-day dependent immune responses. In-vivo studies revealed that the loss of GIV significantly alters the circadian variation in phagocytic activity against E.coli as well as the infiltration of inflammatory macrophages to sites of peritoneal injury. In this thesis, we seek to dissect the extensive role that GIV might play in modulating the circadian rhythm of macrophages and how we might manipulate this new player pharmacologically to improve macrophage immune responses against pathogens.