The number of leukocytes present in circulation varies throughout the day, reflecting bone marrow output and emigration from blood into tissues. Using an organism-wide circadian screening approach, we detected oscillations in pro-migratory factors that were distinct for specific vascular beds and individual leukocyte subsets. This rhythmic molecular signature governed time-of-day-dependent homing behavior of leukocyte subsets to specific organs. Ablation of the gene BMAL1, a transcription factor central to circadian clock function, in endothelial cells or leukocyte subsets demonstrated that rhythmic recruitment is dependent on both microenvironmental and cell-autonomous oscillations. These oscillatory patterns defined leukocyte trafficking in both homeostasis and inflammation and determined detectable tumor burden in blood cancer models. Rhythms in the expression of pro-migratory factors and migration capacities were preserved in human primary leukocytes.
We have identified a broad and rhythmic program that governs the migration patterns of leukocyte subsets throughout the body over the course of the day. We have further defined that an organ- and leukocyte-subset-specific functional rhythmic signature exists, consisting of pro-migratory factors on endothelial cells and leukocytes. Our data demonstrate that rhythmicity in both blood vessels and leukocytes contributes to this process given that a genetically induced lack of a functional clock in either ablates time-of-day differences. We have thus identified an extensive, time-of-day-dependent trafficking zip code that guides migration of leukocytes to organs. Our observations are of particular relevance since we demonstrate rhythms in leukocyte homing to extend to humans.
We have identified the time-of-day dependent traffic routes of leukocytes in the organism. We have characterized the cell-type-specific circadian expression profiles of pro-migratory factors in leukocytes and endothelial cells. We have identified daily rhythms in the expression of pro-migratory factors on leukocyte subsets and endothelial cells of different organs. We have additionally identified a rhythmic and cell-type specific recruitment profile for leukocyte subsets to different organs and identified the oscillatory patterns of genes of the circadian clock in different cell lineages. We have published these results in two Immunity papers in 2017 and 2018, in a Circulation paper in 2019, as well as in several overview articles. We have engaged in many scientific conferences and seminars, allowing the dissemination of these results to a wide audience, including members of the general public and industry. We are now in the process of harnessing these insights to develop chronopharmacological, i.e. time-of-day-dependent, immuno-therapies in the aim to treat or prevent multiple inflammatory diseases.
