TNF-alpha and Ccl2 mediate the immune-circadian interaction in the central nervous system.

JOSÉ MANUEL, DUHART; BELÉN CERLIANI; DIEGO A. GOLOMBEK; FERNANDA R. ROMÁN; IGNACIO AIELLO; JUAN JOSÉ CHIESA; MALENA L. MUL FEDELE; SILVINA RICHARD; NATALIA PALADINO

Palm Harbor, Florida

Congreso; Society for Research on Biological Rhythms; 2016

Society for Research on Biological Rhythms

Daily environmental changes on Earth have imposed the development of circadian clock mechanisms that generate rhythms in physiological and behavioral variables. In mammals, the clock resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts its activity is the light-dark (LD) cycle. Bidirectional interactions between immune and circadian systems have been under intensive study in recent years.According to the World Health Organization, work schedules that imply a desynchronization between the circadian system and environmental factors, such as shift work, represent a risk factor for the development of cancer. In a murine model of melanoma, we have observed that the tumors grew faster in animals under circadian desynchronization schedules than in LD conditions. We observed that proinflammatory cytokines were induced during the day in tumor of animals living in LD conditions, but not in desynchronizated schedules. By the other hand, animals carrying tumors showed a decrease in the percentage of nocturnal activity and in the strength of their locotomor activity rhythms in LD conditions. In these animals, the SCN levels of Tnf-α (Tumor Necrosis Factor-alpha) and the chemokine Ccl2 (Monocyte Chemotactic Protein-1) seems to increase at night in comparison with animals without tumors.In a murine model of acute inflammation by inoculation of systemic low doses of the endotoxin LPS (lipopolysaccharide) we have previously reported that LPS administered at early night induce phase-delays of locomotor activity rhythms. Mice lacking of TNF-α receptor 1 (TNFR1) did not show LPS-induced phase-delays, and the same effect was observed by the intracerebroventricular administration of a Ccl2 synthesis inhibitor. Daily TNFR1 and Ccl2 receptor (CCR2) expression in the SCN of WT mice exhibited increased levels at night, when LPS has a circadian effect. Finally, LPS induced an increase in TNF-α, Ccl2 and Interleukin-6 levels in the SCN both at day and at night.In conclusion, here we show in different murine models of inflammation that the immune-circadian interaction can be mediated by TNF-α and Ccl2. We have also confirmed that circadian desynchronization can affect the development of tumors and that the inflammatory molecules in the tumor are over circadian control.