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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CIRCODE (Cell-type specific mechanisms regulating rhythms in leukocyte homing)

Teaser

Summary

Leukocytes are the key components of the immune system that fight infections and provide tissue repair, yet their migration patterns throughout the body over the course of a day are completely unknown. Circadian, ~24 hour rhythms are emerging as important novel regulators of immune cell migration and function, which impacts inflammatory diseases such as myocardial infarction and sepsis. Altering leukocyte tissue infiltration and activation at the proper times provides an option for therapy that would maximize the clinical impact of drugs and vaccinations and minimize side effects.
We are in the process of creating a four-dimensional map of leukocyte migration to organs in time and space and investigating the molecular mechanisms that regulate cell-type specific rhythms. We are currently functionally defining the daily oscillating molecular signatures of leukocytes and endothelial cells and are thus identifying a circadian traffic code that dictates the rhythmic migration of leukocyte subsets to specific organs under steady-state and inflammatory conditions using pharmacological and genetic tools. We also assess the impact of lineage-specific arrhythmicities on immune homeostasis and leukocyte trafficking using an innovative combination of novel genetic tools. Based on these data we will create a model predicting circadian leukocyte migration to tissues.

Work performed

We have thus far focused on and almost completed the first objective of the proposal, namely the characterization of 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, which is part of the second objective of the proposal. We have also published a manuscript detailing lymphocyte-specific oscillation patterns in lymph nodes and their relevance for immunization reactions and pathogen encounter.

Final results

It is currently very incompletely understood how leukocytes â€“ the critical effector cells of the immune system â€“ circulate within the body over the course of a day. We have thus far defined a novel circadian homing code comprised of molecules involved in the migration of leukocytes across the whole body in time. Our research will form the foundation to develop new time-based therapies to alter leukocyte migration and function and enhance the efficacies of drugs and vaccinations in the clinical setting.