Cis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 limits antibody-mediated neutrophil recruitment

Nat Commun. 2018 Nov 29;9(1):5058. doi: 10.1038/s41467-018-07506-1.

Abstract

Vascular-deposited IgG immune complexes promote neutrophil recruitment, but how this process is regulated is still unclear. Here we show that the CD18 integrin Mac-1, in its bent state, interacts with the IgG receptor FcγRIIA in cis to reduce the affinity of FcγRIIA for IgG and inhibit FcγRIIA-mediated neutrophil recruitment under flow. The Mac-1 rs1143679 lupus-risk variant reverses Mac-1 inhibition of FcγRIIA, as does a Mac-1 ligand and a mutation in Mac-1's ligand binding αI-domain. Sialylated complex glycans on FcγRIIA interact with the αI-domain via divalent cations, and this interaction is required for FcγRIIA inhibition by Mac-1. Human neutrophils deficient in CD18 integrins exhibit augmented FcγRIIA-dependent recruitment to IgG-coated endothelium. In mice, CD18 integrins on neutrophils dampen IgG-mediated neutrophil accumulation in the kidney. In summary, cis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 alters the threshold for IgG-mediated neutrophil recruitment. A disruption of this interaction may increase neutrophil influx in autoimmune diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / metabolism
  • Endothelium / metabolism
  • Glycosylation
  • HEK293 Cells
  • Humans
  • Immunoglobulin G / metabolism
  • Jurkat Cells / metabolism
  • Macrophage-1 Antigen / chemistry
  • Macrophage-1 Antigen / metabolism*
  • Male
  • Mice
  • Nephritis / metabolism
  • Neutrophils / metabolism*
  • Protein Structure, Secondary
  • Receptors, IgG / chemistry
  • Receptors, IgG / metabolism*

Substances

  • FCGR2B protein, human
  • Fc gamma receptor IIA
  • Immunoglobulin G
  • Macrophage-1 Antigen
  • Receptors, IgG