Fc Alpha Receptor I Activation Induces Leukocyte Recruitment and Promotes Aggravation of Glomerulonephritis Through the FcR Gamma Adaptor

Eur J Immunol. 2007 Apr;37(4):1116-28. doi: 10.1002/eji.200636826.

Abstract

Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcRgamma adaptor. They express FcRgamma-associated FcalphaRI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of FcalphaRIgamma in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of FcalphaRI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human FcalphaRI(R209L) that cannot associate with FcRgamma. Like FcalphaRI(wt)-Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. FcalphaRI activation in FcalphaRI(wt), but not in FcalphaRI(R209L), Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred FcalphaRI(wt) Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. FcalphaRI(wt) cross-linking on macrophages activated MAP kinases and production of TNF-alpha and MCP-1. Moreover, IgA-IC from IgAN patients activated FcalphaRI and induced TNF-alpha production. Thus, FcalphaRI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • Antigens, CD / physiology
  • Chemotaxis, Leukocyte / genetics
  • Chemotaxis, Leukocyte / immunology*
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Fc / metabolism*
  • Receptors, Fc / physiology
  • Receptors, IgG / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • Antigens, CD
  • Fc(alpha) receptor
  • Receptors, Fc
  • Receptors, IgG