Lactation-associated macrophages exist in murine mammary tissue and human milk

Abstract

Macrophages are involved in immune defense, organogenesis and tissue homeostasis. Macrophages contribute to the different phases of mammary gland remodeling during development, pregnancy and involution postlactation. Less is known about the dynamics of mammary gland macrophages in the lactation stage. Here, we describe a macrophage population present during lactation in mice. By multiparameter flow cytometry and single-cell RNA sequencing, we identified a lactation-induced CD11c+CX3CR1+Dectin-1+ macrophage population (liMac) that was distinct from the two resident F4/80hi and F4/80lo macrophage subsets present pregestationally. LiMacs were predominantly monocyte-derived and expanded by proliferation in situ concomitant with nursing. LiMacs developed independently of IL-34, but required CSF-1 signaling and were partly microbiota-dependent. Locally, they resided adjacent to the basal cells of the alveoli and extravasated into the milk. We found several macrophage subsets in human milk that resembled liMacs. Collectively, these findings reveal the emergence of unique macrophages in the mammary gland and milk during lactation.

Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer

“…41,42 A population of monocyte-derived macrophages associated with lactation has recently been identified both in the tissue and in milk, termed lactation-induced macrophages (liMacs), which are thought to be involved in immune response. 43 Finally, macrophages are present during involution, and depletion of macrophages was found to be associated with delayed involution and a reduction in apoptotic epithelial cells, suggesting that macrophages are important during the post-lactational involution process. 44 As described above, resident macrophage function is driven by transcriptional and epigenetic mechanisms.…”

“…Macrophages are found in close contact with alveolar structures during pregnancy, and macrophage deficiency is associated with reduced alveolar development during pregnancy 41,42 . A population of monocyte‐derived macrophages associated with lactation has recently been identified both in the tissue and in milk, termed lactation‐induced macrophages (liMacs), which are thought to be involved in immune response 43 . Finally, macrophages are present during involution, and depletion of macrophages was found to be associated with delayed involution and a reduction in apoptotic epithelial cells, suggesting that macrophages are important during the post‐lactational involution process 44 …”

“…Ductal macrophages are found between the epithelial and myoepithelial layers (purple), while stromal macrophages are found in the adipose stroma of the mammary gland. Stromal macrophages are further divided into LYVE‐1 hi MHCII lo macrophages (red) and LYVE‐1 int MHCII hi macrophage (blue) 6,7,43 . Created using Biorender.com.…”

“…Additional studies have demonstrated the presence of LYVE‐1+ macrophages in both the nulliparous mammary gland and during mammary gland involution. LYVE‐1+ macrophages are found in low abundance in virgin mammary tissue and rapidly rise during pregnancy and lactation before regressing during involution 43 . LYVE‐1+ macrophages are present during involution, where they have been shown to incorporate into lymphatic vessels, following which they decrease during the resolution of involution 48 .…”

“…Macrophages first seed the mammary gland during embryonic development and later support development through puberty, the estrous cycle, pregnancy, lactation, and involution. [39][40][41][42][43][44] LN: lymph node, TEB: terminal end bud. Created using Biore nder.…”