Inhibition of antigen trafficking through scavenger receptor A

J Biol Chem. 2012 Feb 17;287(8):5310-6. doi: 10.1074/jbc.M111.316356. Epub 2012 Jan 3.

Abstract

B cell acquisition and presentation of specific autoantigens (auto-Ags) are thought to play an important and complex role in autoimmunity development. We previously identified scavenger receptor A (SR-A) as an early target in altering B cell-mediated autoimmunity. SR-A is highly expressed on professional antigen-presenting cells such as macrophages (MΦs) and dendritic cells (DCs). In this study, we demonstrate that SR-A is responsible for controlling B cell interactions with DCs/MΦs to promote Ag transfer from B cells to DCs/MΦs. We established a high-throughput ELISA-based screen to identify novel SR-A inhibitors, the specificity of which was determined by dose dependence and Biacore surface plasmon resonance testing. We identified small molecule inhibitors (SMIs) able to reduce SR-A-mediated Ag transfer in human cells. In particular, the SMIs prevented SR-A-positive cells from accumulating/loading Ag over time. Furthermore, we determined that one SMI, sennoside B, can reduce SR-A-mediated capture of B cells. Finally, SMI-mediated decreases in Ag transfer or accumulation reduced T cell proliferation in vitro and in vivo. These observations demonstrate that B cell-DC/MΦ interactions are conducive to promoting Ag trafficking between these cell types via SR-A. Inhibitors of SR-A may provide a novel therapeutic strategy in ameliorating autoimmune disease development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthraquinones / pharmacology
  • Antigens / immunology
  • Antigens / metabolism*
  • Autoantigens / immunology
  • Autoantigens / metabolism
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Biological Transport / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Scavenger Receptors, Class A / antagonists & inhibitors*
  • Scavenger Receptors, Class A / metabolism*
  • Senna Extract
  • Sennosides
  • Small Molecule Libraries / pharmacology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Time Factors

Substances

  • Anthraquinones
  • Antigens
  • Autoantigens
  • Scavenger Receptors, Class A
  • Sennosides
  • Small Molecule Libraries
  • Senna Extract