Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll‐like receptor‐9 signalling‐accelerated glomerulonephritis
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 FcαRIR209L/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.