Abstract
Macrophages serve multiple functions including immune regulation, morphogenesis, tissue homeostasis and healing reactions. The current paradigm holds that mammary gland macrophages first arise postnatally during the prepubertal period from the bone marrow-derived monocytes. Here we delineate the origins of tissue-resident mammary gland macrophages using high-dimension phenotypic analyses, cell-fate mapping experiments, gene-deficient mice lacking selective macrophage subtypes, and antibody-based depletion strategies. We show that tissue-resident macrophages are found in mammary glands already before birth, and that the yolk sac-derived and fetal liver-derived macrophages outnumber the adult-derived macrophages in the mammary gland also in the adulthood. In addition, fetal-derived mammary gland macrophages have a characteristic phenotype, display preferential periductal and perivascular localization, and are highly active in scavenging. These findings identify fetal-derived macrophages as the predominant leukocyte type in the adult mammary gland stroma, and reveal previously unknown complexity of macrophage biology in the breast.
Highlights
Macrophages serve multiple functions including immune regulation, morphogenesis, tissue homeostasis and healing reactions
We found that newborn Ccr2−/− and their wild type control mice had similar frequencies of yolk sac (YS)-derived F4/80Hi and fetal liver-derived F4/80Int macrophages in the Mammary gland (MG) (Fig. 2a)
We show that the majority of tissue-resident macrophages in adult MG are derived from the fetal period
Summary
Macrophages serve multiple functions including immune regulation, morphogenesis, tissue homeostasis and healing reactions. Fetal-derived mammary gland macrophages have a characteristic phenotype, display preferential periductal and perivascular localization, and are highly active in scavenging. The recruitment of macrophages is dependent on CCL2/CCR2 and CSF-1 implying the central role of postnatal monocyte influx in the process[23,24,25,26,27,28]. These experiments have led to the prevailing concept that tissueresident macrophages in MG under physiological and pathological conditions are bone marrow-derived cells of postnatal origin[2,29,30]
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