RGD Reference Report - Role of novel rat-specific Fc receptor in macrophage activation associated with crescentic glomerulonephritis. - Rat Genome Database

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Role of novel rat-specific Fc receptor in macrophage activation associated with crescentic glomerulonephritis.

Authors: Page, TH  D'Souza, Z  Nakanishi, S  Serikawa, T  Pusey, CD  Aitman, TJ  Cook, HT  Behmoaras, J 
Citation: Page TH, etal., J Biol Chem. 2012 Feb 17;287(8):5710-9. doi: 10.1074/jbc.M111.260695. Epub 2011 Dec 19.
RGD ID: 11041001
Pubmed: PMID:22184119   (View Abstract at PubMed)
PMCID: PMC3285343   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M111.260695   (Journal Full-text)

Crescentic glomerulonephritis (Crgn) is a complex disease where the initial insult is often the glomerular deposition of antibodies against intrinsic or deposited antigens in the glomerulus. The role of Fc receptors in the induction and progression of Crgn is increasingly recognized, and our previous studies have shown that copy number variation in Fcgr3 partially explains the genetic susceptibility of the Wistar-Kyoto (WKY) rat to nephrotoxic nephritis, a rat model of Crgn. The Fcgr3-related sequence (Fcgr3-rs) is a novel rat-specific Fc receptor with a cytoplasmic domain 6 amino acids longer than its paralogue, Fcgr3. The Fcgr3-rs gene is deleted from the WKY rat genome, and this deletion is associated with enhanced macrophage activity in this strain. Here, we investigated the mechanism by which the deletion of Fcgr3-rs in the WKY strain leads to increased macrophage activation. By lentivirus-mediated gene delivery, we generated stably transduced U937 cells expressing either Fcgr3-rs or Fcgr3. In these cells, which lack endogenous Fcgr3 receptors, we show that Fcgr3-rs interacts with the common Fc-gamma chain but that Fc receptor-mediated phagocytosis and signaling are defective. Furthermore, in primary macrophages, expression of Fcgr3-rs inhibits Fc receptor-mediated functions, because WKY bone marrow-derived macrophages transduced with Fcgr3-rs had significantly reduced phagocytic activity. This inhibitory effect on phagocytosis was mediated by the novel cytoplasmic domain of Fcgr3-rs. These results suggest that Fcgr3-rs may act to inhibit Fcgr3-mediated signaling and phagocytosis and could be considered as a novel mechanism in the modulation of Fc receptor-mediated cell activation in autoimmune diseases.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Fcgr2aRatregulation of Fc receptor mediated stimulatory signaling pathway  IMP  RGD 
Fcgr2aRatregulation of phagocytosis  IMP  RGD 
Fcgr2aRatregulation of tumor necrosis factor production  IMP  RGD 

Cellular Component

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Fcgr2aRatcell surface  IDA  RGD 

Molecular Function

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Fcgr2aRatimmunoglobulin receptor binding  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Fcgr2a  (Fc gamma receptor 2A)

Objects referenced in this article
Gene FCGR2A Fc gamma receptor IIa Homo sapiens
Gene Fcgr3 Fc receptor, IgG, low affinity III Mus musculus

Additional Information