ATG proteins mediate efferocytosis and suppress inflammation in mammary involution

Irina Teplova, Fred Lozy, Sandy Price, Sukhwinder Singh, Nicola Barnard, Robert Cardiff, Raymond B. Birge, Vassiliki Karantza

Research output: Contribution to journalArticle

28 Scopus citations

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 (MEC s) 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 (BEC N1 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 to 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.

Original languageEnglish (US)
Pages (from-to)459-475
Number of pages17
JournalAutophagy
Volume9
Issue number4
DOIs
StatePublished - Jan 1 2013

Keywords

  • Autophagy
  • Dead cell clearance
  • Ductal ectasia
  • Efferocytosis
  • Engulfment
  • Inflammation
  • ITGB5
  • Mammary involution
  • MERTK

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Teplova, I., Lozy, F., Price, S., Singh, S., Barnard, N., Cardiff, R., Birge, R. B., & Karantza, V. (2013). ATG proteins mediate efferocytosis and suppress inflammation in mammary involution. Autophagy, 9(4), 459-475. https://doi.org/10.4161/auto.23164