IL-6 Trans-Signaling Is Critical for Integrating Circadian Rhythms and Neuroimmune Responses to LPS Challenge in Mice

Abstract

Immunological homeostasis relies on a sophisticated bidirectional dialogue between the immune and nervous systems, primarily coordinated by cytokine signaling. These peripheral signals access the central nervous system (CNS) via circumventricular organs and are integrated within the hypothalamus to mount appropriate homeostatic responses. Given that the immune system is under rigorous circadian control, circadian desynchrony—such as constant light exposure—often compromises this coordination, thereby increasing disease vulnerability. This study investigates the hypothesis that interleukin-6 (IL-6) is a pivotal mediator in this neuroimmune dialogue, specifically examining how astrocytic IL-6 trans-signaling modulates hypothalamic activity following an immune challenge. Utilizing male wild-type (WT) and GFAP-sgp130Fc (TG) mice—the latter genetically engineered to express a soluble gp130 fusion protein that selectively binds the IL-6/sIL-6R complex, thereby acting as a specific decoy receptor to inhibit astrocytic IL-6 trans-signaling without altering classical membrane-bound signaling—we assessed physiological and molecular responses under standard LD cycles and constant light (LL) conditions, the latter serving as a model for circadian desynchronization. Our results reveal that TG mice exhibit compromised circadian patterns and significantly altered thermoregulatory responses to lipopolysaccharide (LPS) compared to WT controls. Notably, TG mice under LL conditions showed a complete abolition of the thermoregulatory response to LPS, identifying a critical failure in homeostatic integration when both astrocytic signaling and circadian organization are impaired. Furthermore, c-Fos immunoreactivity within the suprachiasmatic nucleus and paraventricular nucleus indicated a profound suppression of hypothalamic activation in TG animals. Peripheral analysis of hepatic mRNA (IL-1β, IL-6, TLR4) confirmed genotype- and photoperiod-dependent variations, with TG mice displaying a markedly blunted inflammatory profile. These findings underscore the essential role of astrocytic IL-6 trans-signaling in neuroimmune communication and demonstrate that its absence, coupled with circadian disruption, induces a state of “neuronal deafness” that severely compromises the ability of the CNS to respond to inflammatory challenges.