Effect of B7-H4 downregulation induced by Toxoplasma gondii infection on dysfunction of decidual macrophages contributes to adverse pregnancy outcomes

Background: Toxoplasma gondii infection during pregnancy can lead to fetal defect(s) or congenital complications. The inhibitory molecule B7-H4 expressed on decidual macrophages (dM phi) plays an important role in maternal-fetal tolerance. However, the effect of B7-H4 on the function of dM phi during T. gondii infection remains unclear. Methods: Changes in B7-H4 expression on dM phi after T. gondii infection were explored both in vivo and in vitro. B7-H4(-/-) pregnant mice (pregnant mice with B7-H4 gene knockout) and purified primary human dM phi treated with B7-H4 neutralizing antibody were used to explore the role of B7-H4 signaling on regulating the membrane molecules, synthesis of arginine metabolic enzymes and cytokine production by dM phi with T. gondii infection. Also, adoptive transfer of dM phi from wild-type (WT) pregnant mice or B7-H4(-/-) pregnant mice to infected B7-H4(-/-) pregnant mice was used to examine the effect of B7-H4 on adverse pregnancy outcomes induced by T. gondii infection. Results: The results illustrated that B7-H4(-/-) pregnant mice infected by T. gondii had poorer pregnancy outcomes than their wild-type counterparts. The expression of B7-H4 on dM phi significantly decreased after T. gondii infection, which resulted in the polarization of dM phi from the M2 toward the M1 phenotype by changing the expression of membrane molecules (CD80, CD86, CD163, CD206), synthesis of arginine metabolic enzymes (Arg-1, iNOS) and production of cytokines (IL-10, TNF-alpha) production. Also, we found that the B7-H4 downregulation after T. gondii infection increased iNOS and TNF-alpha expression mediated through the JAK2/STAT1 signaling pathway. In addition, adoptive transfer of dM phi from a WT pregnant mouse donor rather than from a B7-H4(-/-) pregnant mouse donor was able to improve adverse pregnancy outcomes induced by T. gondii infection. Conclusions: The results demonstrated that the downregulation of B7-H4 induced by T. gondii infection led to the dysfunction of decidual macrophages and contributed to abnormal pregnancy outcomes. Moreover, adoptive transfer of B7-H4(+) dM phi could improve adverse pregnancy outcomes induced by T. gondii infection.

Automated summary

The downregulation of B7-H4 induced by T. gondii infection leads to dysfunction of decidual macrophages and contributes to abnormal pregnancy outcomes. Moreover, adoptive transfer of B7-H4(+) decidual macrophages can improve adverse pregnancy outcomes induced by T. gondii infection.