Sex differences in hippocampal cytokine networks after systemic immune challenge

Abstract

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 IFNɣ, 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.

Memory deficits in males and females long after subchronic immune challenge

“…In contrast to the delayed memory deficits in males, females showed greater vulnerability to memory impairments in the first week after the immune challenge. This pattern of early and persistent deficits in females in contrast to delayed, broader memory impairments in males is consistent with recent findings from our lab showing more rapid activation and resolution of neuroinflammatory signaling after systemic immune challenge in females compared with males (Speirs & Tronson, 2018). These findings are consistent with sex differences in peripheral immune responses (Furman et al, 2014;Klein & Flanagan, 2016) and differential regulation of neuroimmune activation (Acaz-Fonseca et al, Arevalo, 2015;Bodhankar et al, 2015;Santos-Galindo et al, 2011).…”

“…Given the greater vulnerability of women to memory disorders such as Alzheimer's disease (Snyder et al, 2016), we are particularly interested in the differential impact of subchronic immune challenge on males and females. Sex differences in peripheral responses are well described (Ghosh & Klein, 2017;Scotland, Stables, Madalli, Watson, & Gilroy, 2011) and there is growing evidence for sex differences in neuroimmune responses and function (Estefanía Acaz-Fonseca, Avila-Rodriguez, Garcia-Segura, & Barreto, 2016;Engler et al, 2016;Sorge et al, 2016;Speirs & Tronson, 2018). It is likely, therefore, that males and females are differentially susceptible to memory decline after subchronic immune challenge.…”

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

“…We observed that females showed more changes in hippocampal gene expression after an acute LPS injection compared with males. These findings are consistent with previous findings of sex differences in the neuroimmune response, with differential activation of glial cells (Acaz-Fonseca et al, 2015;Santos-Galindo et al, 2011), and differences in pattern and timing of cytokine production in the hippocampus (Acaz-Fonseca et al, 2015;Santos-Galindo et al, 2011;Speirs and Tronson, 2018;Tonelli et al, 2008). Surprisingly, stronger regulation of gene expression during acute immune challenge in females did not correspond to more enduring dysregulation of baseline gene expression in females.…”

Neuroimmune Activation Drives Multiple Brain States

“…This is a particularly important avenue for research into individual differences and sex differences in susceptibility to immune-related disorders of cognition, memory and emotion (Perry et al, 2016; Snyder et al, 2016; Tronson and Collette, 2017; Choleris et al, 2018; Fisher et al, 2018; Speirs and Tronson, 2018). …”

“…During activation by LPS, for example, whereas cytokines in serum can be hundreds or thousands fold higher than baseline, in the brain, these changes are limited to 1.5–10 fold range (Erickson and Banks, 2011; Biesmans et al, 2013; Speirs and Tronson, 2018) with occasional chemokines showing hundreds of fold increases (e.g., CXCL10, CSF3; Speirs and Tronson, 2018). The difficulty in measuring immune signaling in the brain (and in the periphery, Chovatiya and Medzhitov, 2014) in the baseline state therefore makes it difficult to assess the precise roles in these baseline processes.…”