title: Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor.
abstract: An innate immune response is required for successful implantation and placentation. This is regulated, in part, by the a2 isoform of V-ATPase (a2V) and the concurrent infiltration of M1 (inflammatory) and M2 (anti-inflammatory) macrophages to the uterus and placenta. The objective of the present study was to identify the role of a2V during inflammation-induced preterm labor in mice and its relationship to the regulation of apoptosis and innate immune responses. Using a mouse model of infection-induced preterm delivery, gestational tissues were collected 8 h after intrauterine inoculation on day 14.5 of pregnancy with either saline or peptidoglycan (PGN; a TLR 2 agonist) and polyinosinic-polycytidylic acid [poly(I:C); a TLR3 agonist], modeling Gram-positive bacterial and viral infections, respectively. Expression of a2V decreased significantly in the placenta, uterus, and fetal membranes during PGN+poly(I:C)-induced preterm labor. Expression of inducible NO synthase was significantly upregulated in PGN+poly(I:C)-treated placenta and uterus. PGN+poly(I:C) treatment disturbed adherens junction proteins and increased apoptotic cell death via an extrinsic pathway of apoptosis among uterine decidual cells and spongiotrophoblasts. F4/80(+) macrophages were increased and polarization was skewed in PGN+poly(I:C)-treated uterus toward double-positive CD11c(+) (M1) and CD206(+) (M2) cells, which are critical for the clearance of dying cells and rapid resolution of inflammation. Expression of Nlrp3 and activation of caspase-1 were increased in PGN+poly(I:C)-treated uterus, which could induce pyroptosis. These results suggest that the double hit of PGN+poly(I:C) induces preterm labor via reduction of a2V expression and simultaneous activation of apoptosis and inflammatory processes.
authors.affiliation: Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064;
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jaiswal
authors.forename: Varkha
authors.initials: V
authors.lastname: Agrawal
authors.forename: Timothy
authors.initials: T
authors.lastname: Mallers
authors.forename: Alice
authors.initials: A
authors.lastname: Gilman-Sachs
authors.forename: Emmet
authors.initials: E
authors.lastname: Hirsch
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D007752:Obstetric Labor, Premature / Q000209:etiology / Q000276:immunology* / Q000382:microbiology; D010457:Peptidoglycan / Q000008:administration & dosage; D010920:Placenta / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage; D011247:Pregnancy; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014599:Uterus / Q000276:immunology*
chemical_list: C432920:Atp6v0a2 protein, mouse; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010457:Peptidoglycan; D020170:Caspase 1; D006180:Proton-Translocating ATPases; D011070:Poly I-C