Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM

Immunity. 2005 Jan;22(1):31-42. doi: 10.1016/j.immuni.2004.11.017.


Serum IgA is considered a discrete housekeeper of the immune system with multiple anti-inflammatory functions, whereas IgA-immune complexes mediate inflammatory responses. Here, we identify FcalphaRI as a molecular device that determines the nature of IgA responses. In the absence of sustained aggregation, receptor targeting by serum IgA or anti-FcalphaRI Fab inhibits activating responses of heterologous FcgammaR or FcepsilonRI. The inhibitory mechanism involves recruitment of tyrosine phosphatase SHP-1 to FcalphaRI and impairment of Syk, LAT, and ERK phosphorylation induced by FcepsilonRI engagement. SHP-1 recruitment is dependent on ERK. Conversely, sustained aggregation of FcalphaRI by multimeric ligands stimulates cell activation by recruiting high amounts of Syk and aborting SHP-1 binding. Both types of signals require the FcRgamma-ITAM motif. Anti-FcalphaRI Fab treatment suppresses manifestations of allergic asthma in FcalphaRI transgenic mice. These findings redefine FcalphaRI as a bifunctional inhibitory/activating receptor of the immune system that mediates both anti- and proinflammatory functions of IgA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, CD / physiology*
  • Cell Line
  • Flow Cytometry
  • Humans
  • Immunoglobulin A / metabolism
  • Immunoglobulin A / physiology*
  • Inflammation / immunology*
  • Intracellular Signaling Peptides and Proteins
  • Kinetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phagocytosis
  • Phosphorylation
  • Protein Binding
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / metabolism
  • Receptors, Fc / metabolism
  • Receptors, Fc / physiology*
  • Receptors, IgE / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • Transfection


  • Antigens, CD
  • Fc(alpha) receptor
  • Immunoglobulin A
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Fc
  • Receptors, IgE
  • Recombinant Fusion Proteins
  • Mitogen-Activated Protein Kinases
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn6 protein, mouse