Sex Differences in Macrophage Functions in Middle-Aged Rats: Relevance of Estradiol Level and Macrophage Estrogen Receptor Expression

Abstract

The aim of this study was to examine the influence of sex on age-related changes in phenotype and functional capacity of rat macrophages. The potential role of estradiol as a contributing factor to a sex difference in macrophage function with age was also examined. Thioglycollate-elicited peritoneal macrophages derived from the young (2 months old) and the naturally senescent intact middle-aged (16 months old) male and female rats were tested for cytokine secretion and antimicrobial activity (NO and HO production and myeloperoxidase activity). Serum concentration of estradiol and the expression of estrogen receptor (ER)α and ERβ on freshly isolated peritoneal macrophages were also examined. Decreased secretion of IL-1β and IL-6 by macrophages from middle-aged compared to the young females was accompanied with the lesser density of macrophage ERα expression and the lower systemic level of estradiol, whereas the opposite was true for middle-aged male rats. Macrophages in the middle-aged females, even with the diminished circulating estradiol levels, produce increased amount of IL-6, and comparable amounts of IL-1β, TNF-α, and NO to that measured in macrophages from the middle-aged males. Age-related changes in macrophage phenotype and the antimicrobial activity were independent of macrophage ERα/ERβ expression and estradiol level in both male and female rats. Although our study suggests that the sex difference in the level of circulating estradiol may to some extent contribute to sex difference in macrophage function of middle-aged rats, it also points to more complex hormonal regulation of peritoneal macrophage activity in females.

Macrophage cells secrete factors including LRP1 that orchestrate the rejuvenation of bone repair in mice

“…Many cell types increase protein secretion with senescence 43 – 45 , a process associated with aging, as well as some repair processes 14 , 46 . Whereas we found some proteins secreted at higher levels in older macrophages, interestingly there were far more proteins secreted at higher levels in young cells.…”

“…Whereas we found some proteins secreted at higher levels in older macrophages, interestingly there were far more proteins secreted at higher levels in young cells. Whereas there is little information available on the effect of aging on macrophage cell secretion, a few studies examining secretion of individual proteins with age, also found lower levels of protein secretion of as cells age 14 , 46 . Many of the proteins we found increased in young cells were lysosomal and cell surface proteins.…”

Emerging Evidence of Macrophage Contribution to Hyperinnervation and Nociceptor Sensitization in Vulvodynia

“…Whereas female CD-1 mice require 2–3-fold more morphine for an equivalent analgesic response to males, the difference is abolished in T-cell deficient mice (Rosen et al, 2019). Female rodents have greater abundance of macrophages in peritoneal and pleural cavities, higher TLR expression by resident macrophages and greater production of pro-inflammatory cytokines on macrophage stimulation (Scotland et al, 2011; Ćuruvija et al, 2017). These findings support the view that further investigation into the role of macrophages in chronic pain conditions affecting women is warranted.…”

Immune Tumor Microenvironment in Breast Cancer and the Participation of Estrogen and Its Receptors in Cancer Physiopathology

“…Related to this concept, hormone treatment stimulated NO release in human peripheral monocytes and in a murine macrophage cell line via GPER activation coupled with intracellular calcium influx (54, 55). In line with this, stimulation with LPS in isolated peritoneal macrophages from young female rats resulted in elevated NO release; this effect was not observed in macrophages derived from the middle-aged animals, where circulating E2 levels were diminished (56). Moreover, macrophages produce and use arachidonic acid and its different metabolites for the recognition of pathogens and to enhance or suppress inflammatory response (57).…”

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