title: Adrenergic nerves govern circadian leukocyte recruitment to tissues.
abstract: The multistep sequence leading to leukocyte migration is thought to be locally regulated at the inflammatory site. Here, we show that broad systemic programs involving long-range signals from the sympathetic nervous system (SNS) delivered by adrenergic nerves regulate rhythmic recruitment of leukocytes in tissues. Constitutive leukocyte adhesion and migration in murine bone marrow (BM) and skeletal-muscle microvasculature fluctuated with circadian peak values at night. Migratory oscillations, altered by experimental jet lag, were implemented by perivascular SNS fibers acting on β-adrenoreceptors expressed on nonhematopoietic cells and leading to tissue-specific, differential circadian oscillations in the expression of endothelial cell adhesion molecules and chemokines. We showed that these rhythms have physiological consequences through alteration of hematopoietic cell recruitment and overall survival in models of septic shock, sickle cell vaso-occlusion, and BM transplantation. These data provide unique insights in the leukocyte adhesion cascade and the potential for time-based therapeutics for transplantation and inflammatory diseases.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheiermann
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.forename: Andrew
authors.initials: A
authors.lastname: Chow
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Jang
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.forename: Daigo
authors.initials: D
authors.lastname: Hashimoto
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000320:Adrenergic Fibers / Q000276:immunology / Q000378:metabolism; D059331:Adrenergic Neurons / Q000276:immunology / Q000378:metabolism; D000755:Anemia, Sickle Cell / Q000276:immunology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000378:metabolism; D002940:Circadian Rhythm / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007545:Isoproterenol / Q000008:administration & dosage; D007962:Leukocytes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012772:Shock, Septic / Q000276:immunology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D018925:Chemokines; D011943:Receptors, Adrenergic, beta; D018799:Intercellular Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D007545:Isoproterenol