title: Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis.
abstract: 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.
authors: Department of Internal Medicine, Division of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors: T
authors: T
authors: Watanabe
authors: Y
authors: Y
authors: Kanamaru
authors: C
authors: C
authors: Liu
authors: Y
authors: Y
authors: Suzuki
authors: N
authors: N
authors: Tada
authors: K
authors: K
authors: Okumura
authors: S
authors: S
authors: Horikoshi
authors: Y
authors: Y
authors: Tomino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011961:Receptors, Fc / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011961:Receptors, Fc; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases