CD40 activation induces NREM sleep and modulates genes associated with sleep homeostasis.
The T-cell derived cytokine CD40 ligand is overexpressed in patients with autoimmune diseases. Through activation of its receptor, CD40 ligand leads to a tumor necrosis factor (TNF) receptor 1 (TNFR1) dependent impairment of locomotor activity in mice. Here we report that this effect is explained through a promotion of sleep, which was specific to non-rapid eye movement (NREM) sleep while REM sleep was suppressed. The increase in NREM sleep was accompanied by a decrease in EEG delta power during NREM sleep and by a decrease in the expression of transcripts in the cerebral cortex known to be associated with homeostatic sleep drive, such as Homer1a, Early growth response 2, Neuronal pentraxin 2, and Fos-like antigen 2. The effect of CD40 activation was mimicked by peripheral TNF injection and prevented by the TNF blocker etanercept. Our study indicates that sleep-wake dysregulation in autoimmune diseases may result from CD40 induced TNF:TNFR1 mediated alterations of molecular pathways, which regulate sleep-wake behavior.
Department of Neurology, Inselspital, University Hospital Berne, University of Bern, Bern, Switzerland.
Heidemarie
H
Gast
Andreas
A
Müller
Martin
M
Lopez
Daniel
D
Meier
Reto
R
Huber
Frieder
F
Dechent
Marco
M
Prinz
Yann
Y
Emmenegger
Paul
P
Franken
Thomas
T
Birchler
Adriano
A
Fontana
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000150:complications / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002097:C-Reactive Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D004576:Electromyography; D000068800:Etanercept; D051921:Fos-Related Antigen-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D007074:Immunoglobulin G / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D020178:Sleep Disorders, Circadian Rhythm / Q000150:complications / Q000378:metabolism; D012895:Sleep, REM / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D000099153:Pentraxins
D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D019013:CD40 Antigens; D002352:Carrier Proteins; D051767:Early Growth Response Protein 2; D000068800:Etanercept; D051921:Fos-Related Antigen-2; D000072233:Homer Scaffolding Proteins; D007074:Immunoglobulin G; D007155:Immunologic Factors; D009419:Nerve Tissue Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000099153:Pentraxins; C497327:Egr2 protein, mouse; C497873:Fosl2 protein, mouse; C506236:Tnfrsf1a protein, mouse