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.

巨噬细胞存在于体腔中，维持浆膜稳态并提供免疫监视。腹膜巨噬细胞与腹膜炎、子宫内膜异位症和转移性癌症等病理学病因有关；因此，了解控制他们行为的因素至关重要。通过结合命运图谱技术，我们研究了性别和年龄对小鼠腹膜巨噬细胞分化、周转和功能的影响。我们证明，来自骨髓的腹膜巨噬细胞的性别二态性补充（在男性中较高，在女性中很低）是由性成熟时出现的局部微环境的变化驱动的。群体和单细胞 RNA 测序揭示了男性和女性腹膜巨噬细胞之间基因表达的显着二态性，部分原因是这些群体组成的差异。通过估计不同亚群在腔内的驻留时间并评估单核细胞减少的Ccr2 ^−/−小鼠中二态性随年龄的发展，我们证明腹膜巨噬细胞的关键性别依赖性特征是补给率差异的函数。骨髓，而其他则依赖于局部微环境信号。我们证明，腹膜巨噬细胞的二态性周转导致两性之间预防肺炎球菌腹膜炎的能力存在差异。这些数据强调了考虑性别和年龄对炎症和传染病易感性的重要性。