Abstract
Vertical transmission of the intracellular parasite Toxoplasma gondii (T. gondii) can lead to devastating consequences during gestation. Tim-3, a negative immune regulator, is constitutively expressed on decidual macrophages, but its specific role during T. gondii infection has not yet been explored. In the present study, we discovered that Tim-3 plays an important role in the abnormal pregnancy due to T. gondii infection using Tim-3−/− pregnant mice and anti-Tim-3 neutralizing antibody treated human decidual macrophages. The results showed that abnormal pregnancy outcomes were more prevalent in Tim-3−/− infected pregnant mice than in wild-type infected pregnant mice. Tim-3 expression in decidual macrophages was significantly down-regulated after T. gondii infection both in vitro and in vivo. Tim-3 down-regulation by T.gondii infection could strengthen M1 activation and weaken M2 tolerance by changing the M1 and M2 membrane molecule expression, arginine metabolic enzymes synthesis, and cytokine secretion profiles of decidual macrophages. Moreover, Tim-3 down-regulation by T.gondii infection led to PI3K-AKT phosphorylation inhibition, downstream transcription factor C/EBPβ expression, and SOCS1 activation, which resulted in enzymes synthesis regulation and cytokines secretion. Our study demonstrates that Tim-3 plays an indispensable role in the adverse pregnancy outcomes caused by T. gondii infection.
Highlights
Toxoplasmosis, a common parasitic zoonosis occurring worldwide, is caused by the obligate intracellular protozoan parasite, Toxoplasma gondii (T.gondii) [1]
We showed that functional molecules and cytokines produced by maternal NK cells, DC, and Tregs are affected by T. gondii infection, which contributes to abnormal pregnancy [26,27,28]
Whether Tim-3 participate in abnormal pregnancy outcomes during T. gondii infection and what its precise role is have been unclear
Summary
Toxoplasmosis, a common parasitic zoonosis occurring worldwide, is caused by the obligate intracellular protozoan parasite, Toxoplasma gondii (T.gondii) [1]. The mechanism through which T. gondii infection causes these severe abnormalities during human pregnancy is not clear. Within the maternal-fetal immune system, decidual macrophages, the second largest population of decidual leukocytes during the first trimester (∼20%) after decidual NK cells (∼70%), are required for a successful pregnancy, including trophoblast invasion, tissue and vascular remodeling, and permitting maternal-fetal tolerance throughout gestation [5,6,7]. Our previous study has showed that T. gondii infection causes a bias toward M1 decidual macrophages, contributing to abnormal pregnancy [12]. The downregulation of the inhibitory receptor, LILRB4, can strengthen M1 decidual macrophages activation, and cause severe adverse pregnancy outcomes during T. gondii infection [13]. Whether there is any other immune molecule on macrophage participating in the process and contributing to the adverse pregnancy outcomes during T. gondii infection still needs further exploration
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