A circadian zip code guides leukocyte homing

He, Wenyan (2018): A circadian zip code guides leukocyte homing. Dissertation, LMU München: Medizinische Fakultät

Abstract

Circadian rhythms are important for organisms to anticipate predictable environmental changes. Evidence indicates that the oscillation of murine blood numbers is closely related to the lighting schedule. However, the dynamics and the mechanisms of the migration of leukocyte subsets over 24 hours are unknown. Here, we could show that that numbers of circulating leucocyte subsets exhibit circadian rhythms in murine blood, which was regulated by rhythmic homing, with a co-contribution of both microenvironmental and leukocyte-autonomous oscillations. We identified leukocyte and vascular bed specific surface expression oscillations of adhesion molecules and chemokine receptors over 24 hours. To test the relevance of these oscillations, functional blocking experiments using antibodies or functional blockers directed against pro-migratory molecules were performed. Our data indicate the adhesion molecules CD11a, CD49d and L-selectin and the chemokine receptor CXCR4 on the leukocyte side, as well as VCAM-1 and ICAM-1 on the endothelial side to be important in the rhythmic recruitment process of leukocyte subsets. A stronger blocking effect targeting these molecules was found at night for leukocyte subsets. In the homing experiments, we found donor leukocytes preferentially migrated to organs at night, and that the recruitment process of different leukocyte subsets to various organs could be blocked by distinct inhibitors. We exposed the role of circadian genes in the rhythmic recruitment process using B-cell and myeloid-cell-specific knockouts of the circadian gene Bmal1, which demonstrated altered expression levels of specific oscillatory molecules and leukocyte numbers in tissues, suggesting that rhythmicity in these factors may be directly regulated by the circadian clock. Furthermore, we detected inverse oscillation patterns of human blood cell numbers compared to murine cells as well as of the expression levels of CXCR4 on leukocyte subsets. Together, our data demonstrate that circadian genes control a rhythmic leukocyte- and tissue-specific molecular signature in the expression of pro-migratory factors, which allows for the recruitment of select leukocyte subsets at distinct times.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 22. Mai 2018
• 1. Bericht­erstatter:in: Scheiermann, Christoph