Suprachiasmatic astrocytes modulate the circadian clock in response to TNF-α.
The immune and the circadian systems interact in a bidirectional fashion. The master circadian oscillator, located in the suprachiasmatic nuclei (SCN) of the hypothalamus, responds to peripheral and local immune stimuli, such as proinflammatory cytokines and bacterial endotoxin. Astrocytes exert several immune functions in the CNS, and there is growing evidence that points toward a role of these cells in the regulation of circadian rhythms. The aim of this work was to assess the response of SCN astrocytes to immune stimuli, particularly to the proinflammatory cytokine TNF-α. TNF-α applied to cultures of SCN astrocytes from Per2(luc) knockin mice altered both the phase and amplitude of PER2 expression rhythms, in a phase-dependent manner. Furthermore, conditioned media from SCN astrocyte cultures transiently challenged with TNF-α induced an increase in Per1 expression in NIH 3T3 cells, which was blocked by TNF-α antagonism. In addition, these conditioned media could induce phase shifts in SCN PER2 rhythms and, when administered intracerebroventricularly, induced phase delays in behavioral circadian rhythms and SCN activation in control mice, but not in TNFR-1 mutants. In summary, our results show that TNF-α modulates the molecular clock of SCN astrocytes in vitro, and also that, in response to this molecule, SCN astrocytes can modulate clock gene expression in other cells and tissues, and induce phase shifts in a circadian behavioral output in vivo. These findings suggest a role for astroglial cells in the alteration of circadian timing by immune activation.
Laboratorio de Cronobiología, Universidad Nacional de Quilmes/Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1876 Bernal, Buenos Aires, Argentina.
José M
JM
Duhart
María Juliana
MJ
Leone
Natalia
N
Paladino
Jennifer A
JA
Evans
Oscar
O
Castanon-Cervantes
Alec J
AJ
Davidson
Diego A
DA
Golombek
D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D057906:Circadian Clocks / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D056950:Period Circadian Proteins / Q000096:biosynthesis / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D013493:Suprachiasmatic Nucleus / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha