UC Riverside

Sex is a variable that affects the immune response. Males and females have different innate and adaptive immune responses to pathogens, a fact that affects disease progression and treatment. However, only recently has sex has become more universally taken into account, and a lot of the mechanisms that dictate this variability are still being investigated. Correlative studies show that male and female immunologic responses to different pathogens continues to be different regardless of hormone levels, and suggest innate mechanism that differentiate sex response. Here, we used two different models of peripheral inflammation to study the sex-specific mechanisms of pathogenesis and its brain effects. The first model uses intraperitoneally injected LPS (IP-LPS), to drive systemic inflammation via TLR-4 receptor recognition. Using this model, we show in females but not males, that jejunum increases permeability, which is associated with recruitment of CCR2+ macrophages and robust up regulation of inflammatory gene expression. To test whether macrophage activation was required for these effects, we used TREM2KO mice to “lock” macrophages in homeostatic state. We found that TREM2 deficiency prevented the sex-specific effects of jejunum permeability, CCR2+ macrophage recruitment, and metabolic gene expression. Using CCR2KO mice, we demonstrated that the recruited CCR2+ cell population is directly responsible for functional alterations in the jejunum of IP-LPS treated females. The second model uses Alternaria alternata fungal extract to trigger allergic lung inflammation. Lungs contain nociceptors that relay the inflammatory response to the nuclei of the solitary tract (NTS), which controls breathing rhythms, bronchoconstriction, and can modulate inflammatory responses in the lung. We show males and females differentially regulate excitatory synaptic numbers in the NTS region; females decrease vglut2 and synaptophysin co-localized puncta, while males do not. The NTS also shows a sex-specific activation of protein signaling cascades PI3K/AKT and MAPK. Collectively the two models show how sex differentially impact peripheral immune response in inflammatory models, and how the brain plays a dual role by receiving and influencing that response.