Immunological Aspects of Mammary Involution

Nickerson, S.C.

doi:10.3168/jds.s0022-0302(89)79278-x

Cited by 97 publications

(99 citation statements)

References 34 publications

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“…Another possible reason for the poor development of the MFG-E8 Ϫ/Ϫ mammary gland is the mastitis that was observed in almost all MFG-E8 Ϫ/Ϫ mice soon after the first involution. Mastitis is often caused by bacterial infection, which occurs most frequently during early involution (30). However, our mice were maintained in specific pathogen-free conditions, and mastitis was never found in the WT mice, suggesting that the mastitis in the MFG-E8 Ϫ/Ϫ mice was induced without bacterial infection.…”

Section: Discussionmentioning

confidence: 99%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

120

118

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During the involution of mammary glands, epithelial cells undergo apoptosis and are cleared for the next cycle of lactation. The clearance of apoptotic epithelial cells is mediated by neighboring epithelial cells and by macrophages that migrate into the mammary glands. Here, we report that milk fat globule EGF factor 8 (MFG-E8), a secreted glycoprotein that binds to apoptotic cells by recognizing phosphatidylserine, was expressed by epithelial cells and macrophages in mammary glands and was involved in engulfment of apoptotic cells. A deficiency of MFG-E8 caused the accumulation of a large number of milk fat globules (MFGs) in the mammary ducts during involution, indicating that the excess MFGs were cleared by an MFG-E8-dependent mechanism. The MFG-E8 ؊/؊ mice developed mammary duct ectasia with periductal mastitis, and the redevelopment of the mammary gland for their second litter was impaired. These results demonstrate that MFG-E8-mediated phagocytosis of apoptotic epithelial cells and MFGs is important for efficient involution of mammary glands.exosomes ͉ mastitis ͉ phosphatidylserine M ammary glands are unique mammalian organs that are developed to nurse offspring. For each pregnancy, the glands undergo a cycle of development, lactation, and involution. In each cycle, mammalian epithelial cells proliferate, differentiate, and die. The involution of mammary glands is triggered when the suckling stimulus is lost, usually upon weaning, and milk accumulates in the glands. The involution takes Ϸ10 days in mice and can be divided into two phases (1-3). In the first phase, which is reversible and lasts 48 h after weaning, mammary epithelial cells lose their differentiated function. In the second phase, the basement membranes and extracellular matrix in the mammary glands are degraded by proteases, leading to destruction of the lobular-alveolar architecture of the mammary glands. As involution progresses, mammary epithelial cells are removed and adipocytes concomitantly reappear, and the lobular-alveolar structure is reorganized to approach that of virgin glands (4).During the involution process, epithelial cells undergo apoptosis and are shed into the lumen (5). At the initial stage of involution, these apoptotic cells are thought to be engulfed mainly by neighboring epithelial cells; in the later stage, they seem to be cleared by macrophages that migrate into the gland (3, 6). Milk fat globules (MFGs) are minute globules carrying fat that are secreted from the epithelial cells into the lumen during lactation (7). Upon weaning, many MFGs remain in the lumen, and they seem to be engulfed by epithelial cells lining the lobules in the mammary gland (8). How these epithelial cells and macrophages recognize and engulf apoptotic cells and MFGs has not been well elucidated.Many molecules expressed on the surface of apoptotic cells or phagocytes have been proposed as ligands and receptors for the engulfment of apoptotic cells (9 -11). Mouse MFG EGF factor 8 (MFG-E8), called lactadherin in humans, is a 72-kDa glycoprotein s...

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Section: Discussionmentioning

confidence: 99%

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

120

118

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“…It has been reported that the early period of mammary gland involution coincides with a period of acutely increased susceptibility to intramammary infection (Nickerson, 1989 ;Oliver & Sordillo, 1989). One of the reasons given was that this could be due to the loss of the physical barrier by sloughing of the alveolar epithelium.…”

Section: mentioning

confidence: 99%

Leucocyte phenotypes in involuting and fully involuted mammary glandular tissues and secretions of sheep

et al. 2000

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Mammary glandular tissues and mammary secretions were obtained from sheep at 2-60 d after weaning to study the leucocyte phenotypes associated with mammary involution. From 2-4 d after weaning, neutrophils were the predominant leucocytes in the alveolar and ductal lumina. Lymphocytes were present in the alveolar and ductal epithelium, interalveolar and periductal areas. Most of the lymphocytes in the alveolar and ductal epithelium (IEL) were CD8 + , some were CD45R + and few were CD4 + . In the periductal clusters and in the interalveolar areas most of the lymphocytes were CD4 + . There was a significant increase (P 0n05) in the percentages of CD45R + granulated IEL from 2 to 7 d after weaning, and this paralleled the increase in the percentages of apoptotic cells in the glandular epithelium. By 7-60 d after weaning, most cells within the alveolar and ductal lumina were macrophages followed by predominantly CD8 + lymphocytes. CD8 + lymphocytes were still predominant in the alveolar and ductal epithelium while CD4 + cells were predominant in the interalveolar areas. Very few γδ + T cells were observed at all the stages examined. The cells in the mammary secretions correlated with those observed in the alveolar and ductal lumina. At the early stages of involution, the neutrophils and macrophages were heavily laden with lipid droplets, casein and cellular debris. The most interesting feature was the presence of cells either with extensive cytoplasmic processes (LCA + MHC class II + ) or cytoplasmic veils (LCA + MHC class II + CD1 + ), probably dendritic cells. It is concluded that the cellular constituents of the mammary gland at the latter part of involution may afford the mammary gland more resistance to infection than the lactating gland and the gland at early stages of involution. The CD45R + IEL may trigger apoptotic cell death in the mammary glandular epithelium during mammary involution.Key words : Lactation ; granulated lymphocytes ; mammary regression ; dendritic cells. It has been reported that the early period of mammary gland involution coincides with a period of acutely increased susceptibility to intramammary infection (Nickerson, 1989 ;Oliver & Sordillo, 1989). One of the reasons given was that this could be due to the loss of the physical barrier by sloughing of the alveolar epithelium. Our recent studies (Lee et al. 1996 ;Tatarczuch et al. 1997) excluded this possibility as it was clearly shown that the process of apoptosis enabled the deletion of the alveolar epithelial cells without the loss of the integrity of the epithelial lining of the gland.Our previous studies (Lee et al. 1989) showed thatCorrespondence to Dr C. S. Lee, Department of Veterinary Science, The University of Melbourne, 3010, Victoria, Australia. Fax :j61 3 9344 7374 ; e-mail : c.lee!vet.unimelb.edu.au in the mammary gland of both nonpregnant and pregnant sheep, the great majority of the lymphocytes in the ductal and alveolar epithelium were agranulated and that they belong to the CD8 + CD5 V phenotype follow...

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“…Taken together, these data suggest that involution is associated with an early influx of neutrophils followed closely by macrophages and lymphocytes. It is important to note that since the mammary gland decreases tremendously in size during early involution and milk production stops, any increase in the number of inflammatory cells per tissue section or microliter of ductal secretions may not reflect an increase in the total number of inflammatory cells in the gland, but rather an increase in the concentration of the cell types [37,43]. Even with this caveat in mind, the histological and cytological data suggest that at least during the later stages of involution, inflammatory cells are present within the mammary gland and can contribute to the removal of apoptotic cells and residual milk, thereby facilitating mammary gland remodeling.…”

Section: Evidence Supporting Roles For Professional Phagocytes In Mammentioning

confidence: 99%

Roles of the Innate Immune System in Mammary Gland Remodeling During Involution

Atabai

Sheppard

Werb

2007

J Mammary Gland Biol Neoplasia

106

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Mammary gland involution is a period of intensive tissue remodeling. Over the course of a relatively brief period, a large proportion of the mammary gland epithelium undergoes programmed cell death and is removed by phagocytes. In addition, the gland is cleared of residual milk fat globules as well as milk and adipocytes become the predominant cell type. The role of the immune system in this process has not been clearly defined. Professional phagocytes derived from the immune system can participate in the clearance of apoptotic and autophagic cells, the removal of residual milk components, and the prevention of mastitis during mammary gland involution. However, many of these functions can also be performed by non-professional phagocytes (e.g. mammary epithelial cells). This review will discuss the evidence that supports a role for innate immune cells in mammary gland remodeling during involution.

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Immunological Aspects of Mammary Involution

Cited by 97 publications

References 34 publications

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Leucocyte phenotypes in involuting and fully involuted mammary glandular tissues and secretions of sheep

Roles of the Innate Immune System in Mammary Gland Remodeling During Involution

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