| First Author | Watanabe T | Year | 2011 |
| Journal | Clin Exp Immunol | Volume | 166 |
| Issue | 2 | Pages | 235-50 |
| PubMed ID | 21985370 | Mgi Jnum | J:177862 |
| Mgi Id | MGI:5296413 | Doi | 10.1111/j.1365-2249.2011.04452.x |
| Citation | Watanabe T, et al. (2011) Negative regulation of inflammatory responses by immunoglobulin A receptor (FcalphaRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis. Clin Exp Immunol 166(2):235-50 |
| abstractText | Myeloid FcalphaRI, 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-FcalphaRI 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 FcalphaRI(R209L) /FcRgamma chimeric protein and showed that the monovalent targeting of FcalphaRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated nephritis. Mouse monoclonal anti-FcalphaRI 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)-kappaB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcalphaRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcalphaRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcalphaRI 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. |
