Epithelial cells as phagocytes: apoptotic epithelial cells are engulfed by mammary alveolar epithelial cells and repress inflammatory mediator release.
Clearance of apoptotic cells is critical to tissue homeostasis and resolution of inflammatory lesions. Macrophages are known to remove dying cells and release anti-inflammatory mediators in response; however, many cells traditionally thought of as poor phagocytes can mediate this function as well. In the lactating mammary gland following weaning, alveolar epithelial cell death is massive, yet the gland involutes rapidly, attaining its prepregnancy state in a matter of days. We found histologic evidence of apoptotic cell phagocytosis by viable mammary epithelial cells (MEC) in the involuting mouse mammary gland. Cultured MEC were able to engulf apoptotic cells in vitro, utilizing many of the same receptors used by macrophages, including the phosphatidylserine receptor (PSR), CD36, the vitronectin receptor alpha(v)beta3, and CD91. In addition, MEC, like macrophages, produced TGFbeta in response to stimulation of the PSR by apoptotic cells or the anti-PSR ab 217G8E9, and downregulated endotoxin-stimulated proinflammatory cytokine production. These data support the hypothesis that amateur phagocytes play a significant role in apoptotic cell clearance and its regulation of inflammation.
Monks
J
J
Program in Cell Biology, D509, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Rosner
D
D
Geske
F Jon
FJ
Lehman
L
L
Hanson
L
L
Neville
M C
MC
Fadok
V A
VA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005260:Female; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014886:Weaning
D000906:Antibodies; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C498708:Ptdsr protein, mouse; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C408123:phosphatidylserine receptor