RNA sensing by conventional dendritic cells is central to the development of lupus nephritis

Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):E6195-204. doi: 10.1073/pnas.1507052112. Epub 2015 Oct 28.

Abstract

Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b(+) conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.

Keywords: SLE; TLR7; autoimmunity; dendritic cells; nephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Base Sequence
  • CD11b Antigen / metabolism
  • DNA Primers / genetics
  • Dendritic Cells / metabolism*
  • Flow Cytometry
  • Gene Expression Profiling / methods
  • Humans
  • Image Processing, Computer-Assisted
  • Kidney Glomerulus / cytology
  • Kidney Glomerulus / pathology
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / physiopathology*
  • Mice
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, RNA
  • Statistics, Nonparametric
  • Toll-Like Receptor 7 / metabolism*
  • Up-Regulation*

Substances

  • CD11b Antigen
  • DNA Primers
  • ITGAM protein, human
  • TLR7 protein, human
  • Toll-Like Receptor 7