Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation

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  • Sandahl, Melissa
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Hunter, Debra M
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Strunk, Karen E
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Earp, H. Shelton
    • Affiliation: School of Medicine, Department of Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Cook, Rebecca S
    • Other Affiliation: Department of Cancer Biology, The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Ave., Nashville, TN 37232, USA
Abstract
  • Abstract Background Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis. Results ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium. Conclusion Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.
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  • Article
Rights statement
  • In Copyright
Rights holder
  • Melissa Sandahl et al.; licensee BioMed Central Ltd.
Journal title
  • BMC Developmental Biology
Journal volume
  • 10
Journal issue
  • 1
Page start
  • 122
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1471-213X
Bibliographic citation
  • BMC Developmental Biology. 2010 Dec 30;10(1):122
Publisher
  • BioMed Central Ltd
Access right
  • Open Access
Date uploaded
  • August 23, 2012

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