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

Theranostics. 2021 Oct 25;11(20):9953-9966. doi: 10.7150/thno.63743. eCollection 2021.


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-1β levels, as well as serum triglyceride and creatinine levels. Interestingly, exosomes of Lck-BPI Tg T cells stimulated IL-1β expression of wild-type recipient macrophages. Remarkably, adoptive transfer of BPI-containing exosomes increased serum IL-1β 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.

Keywords: BPI; SLE; T cells; Treg; exosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / metabolism*
  • Blood Proteins / genetics
  • Blood Proteins / metabolism*
  • Cell Differentiation
  • Exosomes / genetics
  • Exosomes / metabolism*
  • Female
  • Gene Expression / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • Inflammation Mediators / metabolism
  • Lupus Erythematosus, Systemic / blood
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / metabolism*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Transcriptome / genetics


  • Antimicrobial Cationic Peptides
  • Blood Proteins
  • Inflammation Mediators
  • bactericidal permeability increasing protein