Decidual Macrophage Functional Polarization during Abnormal Pregnancy due to Toxoplasma gondii: Role for LILRB4

Abstract

During gestation, Toxoplasma gondii infection produces a series of complications including stillbirths, abortions, and congenital malformations. The inhibitory receptor, LILRB4, which is mainly expressed by professional antigen-presenting cells (especially macrophages and dendritic cells) may play an important immune-regulatory role at the maternal–fetal interface. To assess the role of LILRB4 during T. gondii infection, LILRB4−/− and T. gondii infected pregnant mouse models were established. Further, human primary-decidual macrophages were treated with anti-LILRB4 neutralizing antibody and then infected with T. gondii. These in vivo and in vitro models were used to explore the role of LILRB4 in T. gondii-mediated abnormal pregnancy outcomes. The results showed that abnormal pregnancy outcomes were more prevalent in LILRB4−/− infected pregnant mice than in wild-type infected pregnant mice. In subsequent experiments, expression levels of LILRB4, M1, and M2 membrane-functional molecules, arginine metabolic enzymes, and related cytokines were assessed in uninfected, infected, LILRB4-neutralized infected, and LILRB4−/− infected models. The results demonstrated T. gondii infection to downregulate LILRB4 on decidual macrophages, which strengthened M1 activation functions and weakened M2 tolerance functions by changing M1 and M2 membrane molecule expression, synthesis of arginine metabolic enzymes, and cytokine secretion profiles. These changes contributed to abnormal pregnancy outcomes. The results of this study provide not only a deeper understanding of the immune mechanisms operational during abnormal pregnancy, induced by T. gondii infection, but also identify potential avenues for therapeutic and preventive treatment of congenital toxoplasmosis.

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

“…Both stimulation conditions have basal expression of these markers that fluctuate during polarization 72 . Thus, the ratio of CD86 to CD206 expression was used to assess protein changes associated with macrophage polarization 73 . The CD86:CD206 ratio increased significantly in M(IFN-γ) compared with M(IL4/IL13) conditions by 72 hours, while heterogenous expression was observed at earlier time points ( Fig 3D).…”

Lipopolysaccharide-induced premature cervical ripening and inflammation in pregnant mice can be alleviated by nicotine

“…In a mouse model of myocardial infarction, inducing M2 macrophage polarization reduced left ventricular adverse remodeling and improved cardiac function [19]. During pregnancy-related disorders such as miscarriages [35] and spontaneous preterm labor [36], the polarization pattern of decidua macrophages skewed toward M1. Such M1 polarization could result in an excessive pro-inflammatory response at the maternal-fetal interface, and interrupt the normal maintenance of pregnancy.…”

Cellular immunopathogenesis in primary Toxoplasma gondii infection during pregnancy

“…At the maternal‐foetal interface, the immune tolerance environment is maintained by cells with a type II T helper (Th2) phenotype . In normal pregnancy, M2 macrophages are the major decidual macrophage population; these macrophages secrete IL‐10, which promotes immune tolerance . M2 macrophages acquire a Th2 phenotype and express anti‐inflammatory cytokines or chemokines, such as IL‐10 and IL‐4, at the maternal‐foetal interface.…”

“…Expression of Th1 cytokines is upregulated, leading to an imbalance of the Th1/Th2 ratio. It has been reported that T. gondii infection downregulates the expression of leucocyte immunoglobulin‐like receptor B4 (LILRB4) on decidual macrophages, which enhances M1 activation and reduces M2 tolerance by changing the expression of M1 and M2 membrane molecules . M1 macrophages secrete TNF‐α and synthesize iNOS, which promotes a pro‐inflammatory response .…”

“…It has been reported that T. gondii infection downregulates the expression of leucocyte immunoglobulin‐like receptor B4 (LILRB4) on decidual macrophages, which enhances M1 activation and reduces M2 tolerance by changing the expression of M1 and M2 membrane molecules . M1 macrophages secrete TNF‐α and synthesize iNOS, which promotes a pro‐inflammatory response . TNF‐α enhances plasminogen activator inhibitor‐1 (PAI‐1) expression in cytotrophoblasts, which inhibits urokinase‐type PA at the leading edge of trophoblast invasion, inducing apoptosis of trophoblasts .…”