Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor

J Immunol. 2013 Dec 1;191(11):5702-13. doi: 10.4049/jimmunol.1301604. Epub 2013 Oct 25.

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.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Humans
  • Immunity, Innate / drug effects
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred Strains
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Obstetric Labor, Premature / etiology
  • Obstetric Labor, Premature / immunology*
  • Obstetric Labor, Premature / microbiology
  • Peptidoglycan / administration & dosage
  • Placenta / immunology*
  • Poly I-C / administration & dosage
  • Pregnancy
  • Proton-Translocating ATPases / genetics
  • Proton-Translocating ATPases / immunology
  • Proton-Translocating ATPases / metabolism*
  • Uterus / immunology*

Substances

  • Atp6v0a2 protein, mouse
  • Carrier Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Peptidoglycan
  • Caspase 1
  • Proton-Translocating ATPases
  • Poly I-C