The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2018

Altered Treg cell and antigen presenting cell populations are associated with LPS induced fetal loss in pregnant miR-223 deficient mice (#126)

Bihong Zhang 1 , John E Schjenken 1 , Lachlan M Moldenhauer 1 , Simon C Barry 1 , Sarah A Robertson 1
  1. Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia

Maternal immune tolerance of the semi-allogeneic fetus requires CD4+Foxp3+ T-regulatory (Treg) cells, which suppress inflammation and anti-fetal immunity. In mice, expansion of the Treg cell pool is initiated by seminal fluid contact at coitus. Recent studies have demonstrated that microRNAs (miRNA) including miR-223 play a role in the regulation of immune responses. This study aimed to investigate the contribution of miR-223 to maternal immune environment, by evaluating Treg cell and antigen presenting cell activation and proliferation using flow cytometry in miR-223-/- or miR-223+/+ C57Bl/6 females at estrus or d3.5pc mated to Balb/c males (n=10-15/group). miR-223 deficiency resulted in a significant alteration in the Treg cell profile in early pregnancy in the PALN following mating where reductions were observed in the proportion of Treg cells amongst the CD4+ T cell pool (22%, p<0.05) and Treg number (28%, p< 0.05) compared to mated miR-223+/+ females. In the absence of miR-223, a reduction in macrophages as a proportion of total cells (58%, p<0.05) and in the number of activated macrophages (15%, p<0.05) was observed in the PALN on d3.5pc compared to mated miR-223+/+ mice. Additional miR-223-/- and miR-223+/+ mice (n=20=21/group) were administered low dose LPS on d9.5pc, to evaluate pregnancy outcomes. The absence of miR-223 led to altered outcomes in pregnancy following LPS inflammatory challenge, with an 10% reduction in fetal weight and a 19% reduction in the fetal:placental weight ratio in late gestation. LPS administration also significantly increased the resorption rate (8.78-fold, p<0.05) in miR-223-/- females compared to miR-223+/+ females.

Collectively, these data show that the absence of miR-223 alters the maternal immune profile in early pregnancy and this may increase susceptibility to inflammation-induced fetal loss later in gestation. These findings may be relevant to understanding how Treg-associated pregnancy pathologies such as preeclampsia arise in women where reduced miR-223 has been noted.