Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor

Sci Rep. 2015 Mar 23;5:9410. doi: 10.1038/srep09410.

Abstract

Cellular organelles and proteins are degraded and recycled through autophagy, a process during which vesicles known as autophagosomes fuse with lysosomes. Altered autophagy occurs in various diseases, but its role in preterm labor (PTL) is unknown. We investigated the role of autophagic flux in two mouse models of PTL compared to controls: 1) inflammation-induced PTL (IPTL), induced by toll-like receptor agonists; and 2) non-inflammation (hormonally)-induced PTL (NIPTL). We demonstrate that the autophagy related genes Atg4c and Atg7 (involved in the lipidation of microtubule-associated protein 1 light chain 3 (LC3) B-I to the autophagosome-associated form, LC3B-II) decrease significantly in uterus and placenta during IPTL but not NIPTL. Autophagic flux is altered in IPTL, as shown by the accumulation of LC3B paralogues and diminishment of lysosome associated membrane protein (LAMP)-1, LAMP-2 and the a2 isoform of V-ATPase (a2V, an enzyme involved in lysosome acidification). These alterations in autophagy are associated with increased activation of NF-κB and proinflammatory cytokines/chemokines in both uterus and placenta. Similar changes are seen in macrophages exposed to TLR ligands and are enhanced with blockade of a2V. These novel findings represent the first evidence of an association between altered autophagic flux and hyper-inflammation and labor in IPTL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7
  • Autophagy-Related Proteins
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomal-Associated Membrane Protein 2 / metabolism
  • Lysosome-Associated Membrane Glycoproteins / genetics
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Obstetric Labor, Premature / chemically induced
  • Obstetric Labor, Premature / genetics
  • Obstetric Labor, Premature / metabolism*
  • Obstetric Labor, Premature / pathology
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Placenta / drug effects*
  • Placenta / metabolism
  • Poly I-C / pharmacology
  • Pregnancy
  • Signal Transduction
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • Atg7 protein, mouse
  • Autophagy-Related Proteins
  • Lamp1 protein, mouse
  • Lipopolysaccharides
  • Lysosomal-Associated Membrane Protein 2
  • Lysosome-Associated Membrane Glycoproteins
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Atg4C protein, mouse
  • Cysteine Endopeptidases
  • Vacuolar Proton-Translocating ATPases
  • Autophagy-Related Protein 7
  • Poly I-C