Paying the circadian toll: the circadian response to LPS injection is dependent on the Toll-like receptor 4.

PALADINO N; LEONE MJ; PLANO SA; GOLOMBEK DA

Huerta grande

Congreso; I Reunion Conjunta de Neurociencias; 2009

Although there is substantial information regarding the circadian modulation of immunological variables, little is known about the circadian effect of immune factors. Systemic low doses of endotoxin lipopolysaccharide (LPS) delivered at CT15 (Circadian Time 12 corresponds to locomotor activity onset) induce phase-delays of locomotor rhythm in mice. Our aim was to characterize the circadian behavior and LPS- circadian response of TLR4 (LPS receptor)-KO mice (C57bl/10ScCr), and their corresponding control strain mice (C57bl/10ScCn). We observed a free-running period and a light-pulse (100 lux, 10 min) induced phase- delay similar to the one observed in C57bl/6 mice. However, the number of wheel-turns/circadian night was much higher for TLR4KO than for controls (p0.01). LPS administration (50 ug/kg, i.p.) in C57bl/10ScCn controls induced a larger phase-delay than in C57bl/6 (-1.06+0.09 h vs. -0.52+0.21 h, p0.05). The LPS-induced phase-delay in TLR4KO mice (-0.42+0.29 h) was significantly decreased with respect to their specific controls (p0.05). In both control mice the complete inhibition of wheel-running was observed immediately after LPS injection. This inhibition, was absent in TLR4 KO mice (p=0.0038). Since stopping the wheel at CT15 did not induce circadian phase shifts, LPS effects were specific and not directly related to behavioral inhibition. The LPS-induced c-Fos and Per-1 immunoreactivity in the paraventricular hypothalamic nucleous decreased in TLR4 KO mice in comparison with control mice (p0.001). In conclusion, we found a strain dependence of the circadian LPS response, and we showed that both LPS- induced phase-delay, locomotor inhibition and c-Fos and Per-1 induction is mediated by the TLR4 receptor.