Sex, age, and the macrophage
Peritoneal macrophages are known to contribute to the pathology of peritonitis, endometriosis, and cancer, but the effects of age and sex on the biology of these cells are not well understood. Here, Bain et al. show that replenishment of peritoneal macrophages from the bone marrow is much higher in males compared with females. This results in marked sexual dimorphisms in the phenotypic identity of peritoneal macrophages between the sexes, including differential CD209b expression. Age- and sex-associated differences in macrophage turnover also affect resistance to pneumococcal peritonitis. These findings provide insight into the effects of sex and age on peritoneal inflammation and infection.
Macrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the etiology of pathologies including peritonitis, endometriosis, and metastatic cancer; thus, understanding the factors that govern their behavior is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover, and function. We demonstrate that the sexually dimorphic replenishment of peritoneal macrophages from the bone marrow, which is high in males and very low in females, is driven by changes in the local microenvironment that arise upon sexual maturation. Population and single-cell RNA sequencing revealed marked dimorphisms in gene expression between male and female peritoneal macrophages that was, in part, explained by differences in composition of these populations. By estimating the time of residency of different subsets within the cavity and assessing development of dimorphisms with age and in monocytopenic Ccr2−/− mice, we demonstrate that key sex-dependent features of peritoneal macrophages are a function of the differential rate of replenishment from the bone marrow, whereas others are reliant on local microenvironment signals. We demonstrate that the dimorphic turnover of peritoneal macrophages contributes to differences in the ability to protect against pneumococcal peritonitis between the sexes. These data highlight the importance of considering both sex and age in susceptibility to inflammatory and infectious diseases.
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