title: Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution.
abstract: Mammary gland development is dependent on macrophages, as demonstrated by their requirement during the expansion phases of puberty and pregnancy. Equally dramatic tissue restructuring occurs following lactation, when the gland regresses to a state that histologically resembles pre-pregnancy through massive programmed epithelial cell death and stromal repopulation. Postpartum involution is characterized by wound healing-like events, including an influx of macrophages with M2 characteristics. Macrophage levels peak after the initial wave of epithelial cell death, suggesting that initiation and execution of cell death are macrophage independent. To address the role of macrophages during weaning-induced mammary gland involution, conditional systemic deletion of macrophages expressing colony stimulating factor 1 receptor (CSF1R) was initiated just prior to weaning in the Mafia mouse model. Depletion of CSF1R(+) macrophages resulted in delayed mammary involution as evidenced by loss of lysosomal-mediated and apoptotic epithelial cell death, lack of alveolar regression and absence of adipocyte repopulation 7 days post-weaning. Failure to execute involution occurred in the presence of milk stasis and STAT3 activation, indicating that neither is sufficient to initiate involution in the absence of CSF1R(+) macrophages. Injection of wild-type bone marrow-derived macrophages (BMDMs) or M2-differentiated macrophages into macrophage-depleted mammary glands was sufficient to rescue involution, including apoptosis, alveolar regression and adipocyte repopulation. BMDMs exposed to the postpartum mammary involution environment upregulated the M2 markers arginase 1 and mannose receptor. These data demonstrate the necessity of macrophages, and implicate M2-polarized macrophages, for epithelial cell death during normal postpartum mammary gland involution.
authors: School of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Jenean
authors: J
authors: O'Brien
authors: Holly
authors: H
authors: Martinson
authors: Clarissa
authors: C
authors: Durand-Rougely
authors: Pepper
authors: P
authors: Schedin
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D049590:Postpartum Period / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014886:Weaning
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor