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

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Key Messages

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.