title: Altered autophagic flux enhances inflammatory responses during inflammation-induced preterm labor.
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.
authors: Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL.
authors: Varkha
authors: V
authors: Agrawal
authors: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors: Mukesh K
authors: MK
authors: Jaiswal
authors: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors: Timothy
authors: T
authors: Mallers
authors: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors: Gajendra K
authors: GK
authors: Katara
authors: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors: Alice
authors: A
authors: Gilman-Sachs
authors: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA.
authors: Kenneth D
authors: KD
authors: Beaman
authors: 1] Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL [2] Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL.
authors: Emmet
authors: E
authors: Hirsch
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011247:Pregnancy; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000071193:Autophagy-Related Protein 7; D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases; D008070:Lipopolysaccharides; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D011070:Poly I-C; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D025262:Vacuolar Proton-Translocating ATPases; C502661:Atg7 protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C522187:Atg4C protein, mouse