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Systemic Inflammation Affects the CNS in an Age, Duration, and Sex Dependent Manner

Creative Commons 'BY' version 4.0 license

The response to systemic inflammation has been extensively studied. The collective understanding now is that the central nervous system is susceptible to peripheral inflammation and can exhibit changes to concurrent changes to its’ own neuroimmune state. It has been shown that proinflammation from intraperitoneal injection of IP-LPS leads to increased neuroinflammation, but the studies looking at the differences between males and females is currently lacking. Prolonged neuroinflammation is associated with neurodegenerative diseases, and it has been known for some time that these types of diseases show sex dependent proclivities, with females having a higher incidence of diseases like Alzheimer’s disease and frontal lobe dementia. However, this is not the case for all types of inflammation. Allergic inflammation also causes robust peripheral inflammation, but to an otherwise inert substance. Interestingly, this type of inflammation is not associated with increased neuroinflammation. In fact, depending on the brain region, the effect can be seen as a decrease in neuroimmune metrics, like microglia numbers or gene expression in the hippocampus, or an increase, like in the olfactory bulb. Finally, allergic inflammation is also associated with increased prevalence of internalizing disorders like anxiety or neurodevelopmental disorders like autism spectrum disorder. We’ve demonstrated that proinflammation does lead to sex dependent changes in WT C57BL/6J mice, and that these changes are age dependent. It is also shown that the knockout of a microglial specific phagocytic receptor, transient receptor expressed on myeloid cells 2 (TREM2), is capable of inducing sex dependent changes in neuroinflammation and synaptic genes. Additionally, we demonstrate the effects of allergic inflammation by exposing male and female mice to an aerosolized fungal extract of Alternaria particulates. Here we show clear sex differences in gene expression and microglial reactivity in a brain region dependent manner. These effects of inflammation on the CNS may further our understanding of immune to brain interactions and how this may be contextually dependent on the type of stimulant, the sex, and brain region of interest.

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