Do inflammatory cells participate in mammary gland involution? J Mammary Gland Biol Neoplasia
The processes by which the involuting mammary gland clears residual milk and milk fat, as well as apoptotic cells, have gone largely unstudied in the modern literature. Here we review the evidence for and against the involvement of professional phagocytes of hematopoietic lineage in this process. Additionally we present evidence that mammary epithelial cells themselves are capable of phagocytosis and may be responsible for the majority of apoptotic cell and residual milk clearance during murine involution. In this scheme these cells regulate their cytokine production in response to apoptotic cells in a manner similar to other cells, including macrophages. The ensuing model describes a process of involution that actively suppresses an inflammatory response in the gland, allowing for effective tissue remodeling and damage prevention.
Available from: Pierre Lacasse
- "The increase in SCC observed during mammary gland involution is mainly due to recruitment of immune cells, particularly PMNL and macrophages (Monks et al., 2002). These immune cells are involved in ingestion and clearance of cellular debris and residual milk components, such as casein micelles and lipid droplets (Tatarczuch et al., 1997; Monks et al., 2002; Atabai et al., 2007). The faster increase in SCC with CNH intramammary infusions provides additional evidence that the involution process was accelerated by this treatment. "
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ABSTRACT: The transition from the lactation to the dry period in dairy cows is a period of high risk for acquiring new intramammary infections. This risk is reduced when involution of mammary glands is completed. Consequently, strategies that accelerate the involution process after drying-off could reduce the incidence of mastitis. The objective of this study was to assess the effect of 3 different treatments on mammary gland involution. Each quarter of 8 Holstein cows in late lactation was randomly assigned at drying-off to an intramammary infusion of casein hydrolysate (CNH; 70 mg), ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 5.7 g), lactose (5.1 g), or saline 0.9% (control) solutions. Milk samples were collected on the last 2 d before and 1, 3, 5, 7, 10, and 14 d after the last milking for determining concentrations of mammary gland involution markers. Lactoferrin, somatic cell counts (SCC), BSA, and Na(+) concentrations, as well as matrix metalloproteinase-2 and -9 activities gradually increased in mammary secretions during the first 2 wk following the last milking, whereas milk citrate and K(+) concentrations decreased. As involution advanced, the Na(+):K(+) ratio increased, whereas the citrate:lactoferrin ratio decreased. Compared with mammary secretions from control quarters, mammary secretions of quarters infused with CNH had higher SCC on d 1, 3, 5, and 7, and greater BSA concentrations on d 1, 3, and 5. Similarly, the CNH treatment induced a faster increase in lactoferrin concentrations, which were greater than in milk from control quarters on d 3, 5, and 7 after drying-off. Milk citrate concentrations were unaffected by CNH but the citrate:lactoferrin ratio was lower in CNH-treated quarters on d 3 and 5 than in control quarters. Moreover, CNH treatment hastened the increase in Na(+) concentration and in the Na(+):K(+) ratio on d 1. Infusion of CNH also led to an increase in proteolytic activities, with greater matrix metalloproteinase 9 activities on d 1 and 3. The EGTA infusion increased SCC above that of control quarters on d 1 and 3 but it had no effect on the other parameters. Lactose infusion had no effect on any of the involution markers. In this study, intramammary infusions of CNH were the most efficient treatment to accelerate mammary gland involution, suggesting a potential role of CNH as a local milk secretion inhibitor during milk stasis.
Available from: PubMed Central
- "Historically, studies in dairy animals (cow, sheep and goat) have described neutrophil and macrophage infiltration during the process of mammary gland involution , , . Microarray studies in the mouse also support an inflammatory component to involution , . "
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ABSTRACT: Post-lactation mammary involution is a homeostatic process requiring epithelial apoptosis and clearance. Given that the deficiency of the extracellular metalloproteinase inhibitor TIMP3 impacts epithelial apoptosis and heightens inflammatory response, we investigated whether TIMP3 regulates these distinct processes during the phases of mammary gland involution in the mouse. Here we show that TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation and onset of mitochondrial apoptosis. This accelerated first phase of involution includes faster loss of initiating signals (STAT3 activation; TGFβ3) concurrent with immediate luminal deconstruction through E-cadherin fragmentation. Epithelial apoptosis is followed by accelerated adipogenesis and a greater macrophage and T-cell infiltration in Timp3(-/-) involuting glands. Crossing in Tnf deficiency abrogates caspase 3 activation, but heightens macrophage and T-cell influx into Timp3(-/-) glands. The data indicate that TIMP3 differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution. An understanding of the molecular factors and wound healing microenvironment of the postpartum mammary gland may have implications for understanding pregnancy-associated breast cancer risk.
Available from: cshlp.org
- "Instead macrophage recruitment is only observed 3– 4 days postweaning and instead of professional phagocytes, the removal of the early apoptotic bodies is effected through autophagy by adjacent epithelial cells (Monks and Henson 2009). In mice there is also evidence of neutrophils that are recruited before macrophages and, these cells together with macrophages are scattered through the interstitum and in the alveolar spaces (Monks et al. 2002; Atabai et al. 2007). In the human, cells bearing the pan-leukocytic marker CD45, are also found abundantly in the involuting gland (O'Brien and Schedin 2009). "
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ABSTRACT: Leukocytes, of both the innate and adaptive lineages, are normal cellular components of all tissues. These important cells not only are critical for regulating normal tissue homeostasis, but also are significant paracrine regulators of all physiologic and pathologic tissue repair processes. This article summarizes recent insights regarding the trophic roles of leukocytes at each stage of mammary gland development and during cancer development, with a focus on Murids and humans.
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