TNF-ALPHA AND CCL2 MEDIATE THE IMMUNE-CIRCADIAN INTERACTION IN THE CENTRAL NERVOUS SYSTEM

MUL FEDELE, MALENA; DUHART, JOSÉ MANUEL; ROMÁN, FERNANDA; CHIESA, JUAN JOSÉ; GOLOMBEK, DIEGO; PALADINO, NATALIA; CERLIANI, MARÍA BELÉN; RICHARD, SILVINA MARIEL;

RIO DE JANEIRO

Congreso; Congreso; IBRO - 9th World Congress International Brain Research Organization; 2015; 2015

IBRO

The master mammalian clock resides in the hypothalamic suprachiasmatic nuclei (SCN), and the principal signal that adjusts its activity is the light-dark cycle. Bidirectional interactions between the immune and the circadian systems have been under intensive study in recent years. Circadian disruption affects immune responses and might even represent a risk factor for the development of cancer. Here we describe such changes in murine models of melanoma and acute inflammation.Tumoral growth of animals subjected to a protocol of circadian desynchronization was faster than those of animals in normal light conditions (LD); and the mRNA expression of the clock genes Period (Per) 1 and 2 was reduced in the tumors of these animals, too. Proinflammatory response (measured by Interleuquin-6 (IL-6) induction) was higher during the day in animals living in LD, but did not vary in those subjected to circadian desynchronization. In addition, mRNA levels of the chemokine Ccl2 (MCP1) in the SCN of animals increased in response to the tumor.We have previously reported that systemic low doses of the endotoxin lipopolysaccharide (LPS) administered at CT15 (Circadian Time 12: locomotor activity onset) induce phase-delays of locomotor activity rhythms in mice. We also observed that mice lacking the TNF-α receptor 1 (TNFR1) did not show this LPS-induced circadian effect, and that the endotoxin did not induce cFos and Per2 expression in the SCN, nor Per1 expression in the paraventricular hypothalamic nucleus as compared to wild type (WT) mice. Here we show that central administration of a CCL2 synthesis inhibitor blocked LPS-induced phase shifts. We also analyzed daily TNFR1 and CCL2 receptor (CCR2) expression in the SCN of WT mice, which exhibited increased levels at night. Finally, peripheral inoculation of LPS induced an increase in TNF-α, IL-6 and CCL2 in the SCN and PVN both at day and at night.In conclusion, here we show that the bidirectional interaction between the immune and circadian systems can be mediated by TNF-α and CCL2, in different murine models of peripheral inflammation. We have also confirmed that circadian desynchronization can affect the development of a tumor and that the inflammatory molecules present in the tumor are under circadian control.