title: Nuclear receptor REV-ERBα mediates circadian sensitivity to mortality in murine vesicular stomatitis virus-induced encephalitis.
abstract: Certain components and functions of the immune system, most notably cytokine production and immune cell migration, are under circadian regulation. Such regulation suggests that circadian rhythms may have an effect on disease onset, progression, and resolution. In the vesicular stomatitis virus (VSV)-induced encephalitis model, the replication, caudal penetration, and survivability of intranasally applied VSV depends on both innate and adaptive immune mechanisms. In the current study, we investigated the effect of circadian time of infection on the progression and outcome of VSV-induced encephalitis and demonstrated a significant decrease in the survival rate in mice infected at the start of the rest cycle, zeitgeber time 0 (ZT0). The lower survival rate in these mice was associated with higher levels of circulating chemokine (C-C motif) ligand 2 (CCL2), a greater number of peripherally derived immune cells accumulating in the olfactory bulb (OB), and increased production of proinflammatory cytokines, indicating an immune-mediated pathology. We also found that the acrophase of molecular circadian clock component REV-ERBα mRNA expression in the OB coincides with the start of the active cycle, ZT12, when VSV infection results in a more favorable outcome. This result led us to hypothesize that REV-ERBα may mediate the circadian effect on survival following VSV infection. Blocking REV-ERBα activity before VSV administration resulted in a significant increase in the expression of CCL2 and decreased survival in mice infected at the start of the active cycle. These data demonstrate that REV-ERBα-mediated inhibition of CCL2 expression during viral-induced encephalitis may have a protective effect.
authors.affiliation: Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Khatuna
authors.initials: K
authors.lastname: Gagnidze
authors.affiliation: Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Kaitlyn H
authors.initials: KH
authors.lastname: Hajdarovic
authors.affiliation: Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065;
authors.forename: Marina
authors.initials: M
authors.lastname: Moskalenko
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164.
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Karatsoreos
authors.affiliation: Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@rockefeller.edu bulloch@mail.rockefeller.edu.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.affiliation: Neuroimmunology and Inflammation Program, The Rockefeller University, New York, NY 10065; Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10065; mcewen@rockefeller.edu bulloch@mail.rockefeller.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Bulloch
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004660:Encephalitis / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology; D009026:Mortality; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology; D018116:Vesiculovirus / Q000276:immunology*
chemical_list: D016207:Cytokines; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056926:CLOCK Proteins
keywords: circadian; immune response; inflammation; monocytes; vesicular stomatitis virus