HBV-Associated Immune Remodeling of TNFSF10⁺ Monocytes Through the LPAR3-GALNT4 Axis During Pregnancy

Hepatitis B virus (HBV) infection can lead to adverse pregnancy outcomes, and monocytes may contribute to immune dysregulation associated with HBV-related pregnancy complications. However, the underlying mechanisms by which HBV influences monocyte function during pregnancy complications remain poorly understood.

Peripheral blood mononuclear cells (PBMCs) from HBV-infected and uninfected pregnant women were analyzed using flow cytometry. RNA sequencing (RNA-seq) was performed in anti-TNFSF10 antibody-blocked PBMCs and LPAR3-overexpressing THP-1 cells. LPAR3 was overexpressed in THP-1 cells, followed by cell adhesion, migration, flow cytometry, and immunofluorescence.

Flow cytometry analysis of PBMCs from HBV-infected pregnant women revealed a significant reduction in TNFSF10⁺ monocytes compared with uninfected controls. Transcriptomic analysis of anti-TNFSF10 antibody-incubated PBMCs showed that LPAR3 was significantly upregulated in TNFSF10⁺ cells, with enrichment of pathways related to immune regulation and pregnancy-associated biological processes and innate immune responses. Hepatitis B virus X (HBx) overexpression impaired THP-1 cell adhesion and migration, and reduced TNFSF10⁺ monocyte-like characteristics, which were partially restored by LPAR3 overexpression. RNA-seq of LPAR3 overexpressing THP-1 cells revealed significant activation of immune and inflammatory signaling pathways. Furthermore, LPAR3 overexpression increased the expression of the glycosylation-related gene GALNT4, and GALNT4 restoration partially rescued HBx-induced impairment of monocyte adhesion and migration.

LPAR3 may contribute to the regulation of monocyte functional states and TNFSF10⁺ monocyte-like characteristics, potentially contributing to immune dysregulation, highlighting LPAR3 as a potential target for immune monitoring and mechanistic exploration during HBV-associated pregnancy.

Hepatitis B virus (HBV) infection is associated with adverse pregnancy outcomes, and monocytes play a critical role in maternal immune regulation. However, the mechanisms by which HBV alters monocyte function and contributes to pregnancy complications remain unclear. This study identifies LPAR3 as a regulator of monocyte functional states and TNFSF10+ monocyte-like characteristics. HBV infection impairs monocyte adhesion and migration, which can be partially rescued by LPAR3 overexpression. LPAR3 may serve as a potential target for immune monitoring and mechanistic exploration in HBV-associated pregnancy, providing insights into immune dysregulation during maternal HBV infection.