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Sex differences in hippocampal cytokines after systemic immune challenge

Illness or injury causes an inflammatory state consisting of activation of immune cells and increased production of cytokines in the periphery and in the brain, resulting changes in physiological processes, behavior, and cognition. The immune and neuroimmune response consist of a tightly controlled activation and resolution of cytokine networks, the precise patterns of which are determined, in part, by the immune stimulus. Importantly, the pattern of cytokines, rather than the presence of any individual cytokine, determines the functional outcome of immune signaling. In this project, we hypothesized that given sex differences in behavioral responses to immune challenge, the patterns of cytokine activation induced in the hippocampus after a systemic immune challenge differ between males and females. We examined 32 cytokines in the hippocampus and periphery of male and female mice 2, 6, 24, 48, and 168 hours after an acute systemic injection of lipopolysaccharides (LPS; 250μg/kg). All animals showed resolution of the neuroimmune response 168 hours after immune challenge Males and females differed in the specific cytokines activated in the hippocampus, the magnitude of elevation, and the timecourse of activation and resolution of neuroimmune signaling. Briefly, male-specific elevations included IFNγ, CSF1 (M-CSF) and CSF2 (GM-CSF), and the regulatory cytokine IL-10, whereas female-specific activation included the IL-2 family and the regulatory IL-4. Females showed rapid elevation and resolution of the hippocampal immune response, with cytokine levels peaking at 2 and 6 hours after immune challenge. In contrast, males showed slower and more persistent activation, with peaks at 6-24 hours. These findings demonstrate that sex differences in neuroimmune response are not limited to the intensity of the cytokine response, but more importantly differs in the cytokine networks activated. These findings suggest that delineating the broad, sex-specific patterns of cytokine activity in the brain is critical for understanding of the role of neuroimmune signaling in neural function.