Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice

Abstract

Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

Sex‐specific aging in animals: Perspective and future directions

“…Sex differences in aging could also involve tissue‐specific pathophysiological mechanisms affecting specific organs, including sex‐specific organs, and resulting in age‐related pathologies (for an example of this in Drosophila , see Regan et al, 2016 ). While some data from model organisms exist for some of the molecular drivers (Fischer & Riddle, 2018 ; Menees et al, 2021 ; Mitchell et al, 2016 ; Rodriguez‐Fernandez et al, 2020 ; Tsurumi & Li, 2020 ), comprehensive investigations across taxa are lacking. Thus, the molecular pathways involved in generating sex differences in aging could be diverse and are poorly understood.…”

Sex differences in the aging murine urinary bladder and influence on the tumor immune microenvironment of a carcinogen-induced model of bladder cancer

“…In both humans and mice, B cells are known to exhibit age-related sex differences [ 12 , 32 ]. With advancing immunologic and biologic aging, peripheral pools of B cells show significant decline with a simultaneous increase in mucosal surfaces.…”

Thermoregulatory Dynamics Reveal Sex-Specific Inflammatory Responses to Experimental Autoimmune Encephalomyelitis in Mice: Implications for Multiple Sclerosis-Induced Fatigue in Females

“…Moreover, MS is accompanied by leukocyte infiltration to the central nervous system (CNS), which coincides with production of cytokines and vasoactive substances that in turn affect demyelination and neuronal degeneration (Göbel, Ruck, & Meuth, 2018). A thermoregulatory response to cytokine activation appears to be a disease tolerance defense strategy (Schieber & Ayres, 2016), while both pro- and anti-inflammatory cytokine release as correlates of thermoregulation act in a sex-dependent manner (Menees et al, 2021; Russi, Ebel, Yang, & Brown, 2018; van den Broek, Damoiseaux, De Baets, & Hupperts, 2005; Zhang et al, 2012) arguably via the influence of sex hormones (Klein & Flanagan, 2016). The significant splenomegaly in females may be indicative of modifications in the number and distribution of immune cells within the spleen (Menees et al, 2021) and/or more myeloid-derived suppressor cells (MDSCs) in the spleen that lead to a greater infiltration of the CNS (Melero-Jerez et al, 2020) in females.…”