title: ATG proteins mediate efferocytosis and suppress inflammation in mammary involution.
abstract: Involution is the process of post-lactational mammary gland regression to quiescence and it involves secretory epithelial cell death, stroma remodeling and gland repopulation by adipocytes. Though reportedly accompanying apoptosis, the role of autophagy in involution has not yet been determined. We now report that autophagy-related (ATG) proteins mediate dead cell clearance and suppress inflammation during mammary involution. In vivo, Becn1(+/-) and Atg7-deficient mammary epithelial cells (MECs) produced 'competent' apoptotic bodies, but were defective phagocytes in association with reduced expression of the MERTK and ITGB5 receptors, thus pointing to defective apoptotic body engulfment. Atg-deficient tissues exhibited higher levels of involution-associated inflammation, which could be indicative of a tumor-modulating microenvironment, and developed ductal ectasia, a manifestation of deregulated post-involution gland remodeling. In vitro, ATG (BECN1 or ATG7) knockdown compromised MEC-mediated apoptotic body clearance in association with decreased RAC1 activation, thus confirming that, in addition to the defective phagocytic processing reported by other studies, ATG protein defects also impair dead cell engulfment. Using two different mouse models with mammary gland-associated Atg deficiencies, our studies shed light on the essential role of ATG proteins in MEC-mediated efferocytosis during mammary involution and provide novel insights into this important developmental process. This work also raises the possibility that a regulatory feedback loop exists, by which the efficacy of phagocytic cargo processing in turn regulates the rate of engulfment and ultimately determines the kinetics of phagocytosis and dead cell clearance.
authors: University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ, USA.
authors: Irina
authors: I
authors: Teplova
authors: Fred
authors: F
authors: Lozy
authors: Sandy
authors: S
authors: Price
authors: Sukhwinder
authors: S
authors: Singh
authors: Nicola
authors: N
authors: Barnard
authors: Robert D
authors: RD
authors: Cardiff
authors: Raymond B
authors: RB
authors: Birge
authors: Vassiliki
authors: V
authors: Karantza
mesh_terms: D000483:Alleles; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002461:Cell Line, Transformed; D004108:Dilatation, Pathologic / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008894:Milk Proteins / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C502661:Atg7 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C490919:Mfge8 protein, mouse; D008869:Microtubule-Associated Proteins; D008894:Milk Proteins; D010718:Phosphatidylserines; D020744:rac GTP-Binding Proteins; D000071193:Autophagy-Related Protein 7
keywords: ITGB5; MERTK; autophagy; dead cell clearance; ductal ectasia; efferocytosis; engulfment; inflammation; mammary involution
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