Sex differences and similarities in the neuroimmune response to central administration of poly I:C

Abstract

Background The neuroimmune system is required for normal neural processes, including modulation of cognition, emotion, and adaptive behaviors. Aberrant neuroimmune activation is associated with dysregulation of memory and emotion, though the precise mechanisms at play are complex and highly context dependent. Sex differences in neuroimmune activation and function further complicate our understanding of its roles in cognitive and affective regulation. Methods Here, we characterized the physiological sickness and inflammatory response of the hippocampus following intracerebroventricular (ICV) administration of a synthetic viral mimic, polyinosinic:polycytidylic acid (poly I:C), in both male and female C57Bl/6N mice. Results We observed that poly I:C induced weight loss, fever, and elevations of cytokine and chemokines in the hippocampus of both sexes. Specifically, we found transient increases in gene expression and protein levels of IL-1α, IL-1β, IL-4, IL-6, TNFα, CCL2, and CXCL10, where males showed a greater magnitude of response compared with females. Only males showed increased IFNα and IFNγ in response to poly I:C, whereas both males and females exhibited elevations of IFNβ, demonstrating a specific sex difference in the anti-viral response in the hippocampus. Conclusion Our data suggest that type I interferons are one potential node mediating sex-specific cytokine responses and neuroimmune effects on cognition. Together, these findings highlight the importance of using both males and females and analyzing a broad set of inflammatory markers in order to identify the precise, sex-specific roles for neuroimmune dysregulation in neurological diseases and disorders.

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

“…Neuroinflammation is a strong contributor in AD pathophysiology; however, the impact of glial cell sexual dimorphism in the neuroinflammatory response is still yet fairly unknown. Studies characterizing the neuroinflammatory response in male and female C57Bl/6 N mice suggest that type 1 interferons could be one of the potential sex-mediating cytokines that influencing cognition [ 548 ].…”

“…Reduced neuronal outgrowth and synaptic density -In vitro: [447][448][449] -Mice: APOE4 knock-in [234] Impaired synaptic plasticity (Long term potentiation) -In vitro: [452] -Mice: APOE knock-in [453] Poor learning and memory -Mice: APOE4 knock-in [456][457][458] Autophagy/Endosomes Decreased/impaired autophagy and mitophagy -In vitro: [470] -Mice: APOE4 knock-in [486] Dysregulated endosomal-lysosomal pathway -Mice: APOE4 knock-in [518] Enlarged endosomes -Humans: [481] -Mice: APOE4 knock-in [518] Reduced mRNA levels of autophagy markers -Humans: [489] Fernández-Calle et al Molecular Neurodegeneration (2022) 17 :62 sexual dimorphism in the neuroinflammatory response is still yet fairly unknown. Studies characterizing the neuroinflammatory response in male and female C57Bl/6 N mice suggest that type 1 interferons could be one of the potential sex-mediating cytokines that influencing cognition [548].…”

Neuroprotective Role of Lactoferrin during Early Brain Development and Injury through Lifespan

“…In a complimentary way to human cohorts, animal models enable strengthening of the causal link between perinatal inflammation and neurodevelopmental impairment [ 119 , 120 , 121 ]. The administration of immunostimulants, such as lipopolysaccharide (LPS) and poly I:C, to pregnant dams has been used to model congenital neurological disorders showing social abnormalities associated with autism spectrum disorder [ 119 , 122 ], cerebral palsy [ 123 , 124 ], white matter injury [ 78 ], and a large array of behavioral abnormalities, according to the gestational age and regimen used [ 125 , 126 ]. Postnatal administration of LPS is also often used to model abnormalities related to neurodevelopment [ 119 , 122 ], with outcomes being dependent on postnatal age, dose and regimen.…”

Animal Models for Neuroinflammation and Potential Treatment Methods

“…Neuroinflammation is involved in the onset and/or progression of several neurodegenerative and neuropsychiatric disorders (12)(13)(14)(15)(16) and is facilitated by microglia activation and elevated expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) (17)(18)(19)(20). Studies using animal models have shown that systemic and central administration of lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (poly I:C) can induce neuroinflammation through upregulation of proinflammatory cytokines and glial activation (21)(22)(23)(24)(25)(26)(27). These models can be used for evaluating the anti-inflammatory potential of therapeutics, healthy foods, and nutraceutical products.…”