Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis

Clin Exp Immunol. 2011 Nov;166(2):235-50. doi: 10.1111/j.1365-2249.2011.04452.x.


Myeloid FcαRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent. Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcαRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express FcαRI(R209L) /FcRγ chimeric protein and showed that the monovalent targeting of FcαRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated nephritis. Mouse monoclonal anti-FcαRI MIP8a Fab improved urinary protein levels and reduced the number of macrophages and immunoglobulin deposition in the glomeruli. Monovalent targeting using MIP8a Fab attenuates the TLR-9 signalling pathway and is associated with phosphorylation of extracellular signal-related protein kinases [extracellular signal-regulated kinase (ERK), P38, c-Jun N-terminal kinase (JNK)] and the activation of nuclear factor (NF)-κB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcαRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcαRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcαRI Fab as a negative regulator in controlling the magnitude of the innate immune response and a new type of anti-inflammatory drug for treatment of kidney disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD / immunology*
  • Antigens, CD / metabolism
  • Cell Line
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / metabolism
  • Glomerulonephritis / pathology
  • Humans
  • Immunoglobulin A / immunology*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Kidney / immunology
  • Kidney / pathology
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Oligodeoxyribonucleotides / pharmacology
  • Protein Tyrosine Phosphatases / metabolism
  • Receptors, Fc / immunology*
  • Receptors, Fc / metabolism
  • Signal Transduction
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Antibodies, Monoclonal
  • Antigens, CD
  • Fc(alpha) receptor
  • Immunoglobulin A
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Receptors, Fc
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatases