BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus

Background: Serum-derived exosomes are correlated with disease severity of human systemic lupus erythematosus (SLE). The proteins in the T-cell-derived exosomes from SLE patients could contribute to inflammation. Methods: We characterized proteins of T cell-derived exosomes from SLE patients and healthy controls by proteomics. To study the potential pathogenic role of the identified exosomal protein, we generated and characterized T-cell-specific transgenic mice that overexpressed the identified protein in T cells using immunohistochemistry, immunoblotting, and single-cell RNA sequencing. Results: We identified an overexpressed protein, bactericidal/permeability-increasing protein (BPI), in SLE T cells and T-cell-derived exosomes. T-cell-specific BPI transgenic (Lck-BPI Tg) mice showed multi-tissue inflammation with early induction of serum IL-113 levels, as well as serum triglyceride and creatinine levels. Interestingly, exosomes of Lck-BPI Tg T cells stimulated IL-113 expression of wild-type recipient macrophages. Remarkably, adoptive transfer of BPI-containing exosomes increased serum IL-113 and autoantibody levels in recipient mice. The transferred exosomes infiltrated into multiple tissues of recipient mice, resulting in hepatitis, nephritis, and arthritis. ScRNA-seq showed that Lck-BPI Tg T cells displayed a decrease of Treg population, which was concomitant with ZFP36L2 upregulation and Helios downregulation. Furthermore, in vitro Treg differentiation was reduced by BPI transgene and enhanced by BPI knockout. Conclusions: BPI is a negative regulator of Treg differentiation. BPI overexpression in T-cell-derived exosomes or peripheral blood T cells may be a biomarker and pathogenic factor for human SLE nephritis, hepatitis, and arthritis.

Automated summary

This study found that a protein called bactericidal/permeability-increasing protein (BPI) is overexpressed in T cells and T cell-derived exosomes of SLE patients. BPI may serve as a biomarker and pathogenic factor for SLE nephritis, hepatitis, and arthritis, as it is associated with multi-tissue inflammation and modulation of Treg cell differentiation.