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.
Highlights
Vascular-deposited IgG immune complexes promote neutrophil recruitment, but how this process is regulated is still unclear
CD18 integrin binding to ligand relies on allosteric changes transmitted to and from the ligand binding αI-domain, which has a divalent cation in the metal ion dependent adhesion site (MIDAS) that coordinates acidic residues in the ligand
The ratio of FcγRIIA to Mac-1 and LFA-1 was higher in the J-IIA Mac[1] and J-IIA LFA1 than in healthy, normal human and mouse neutrophils, so the impact of Mac-1 and LFA-1 on FcγRIIA may be underestimated in these cells (Supplementary Figure 1A)
Summary
Vascular-deposited IgG immune complexes promote neutrophil recruitment, but how this process is regulated is still unclear. 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. We studied the mechanisms that regulate FcγRIIA mediated neutrophil recruitment to deposited immune complexes, potentially one of the earliest steps of inflammation and subsequent tissue damage in autoimmune disease[15]. Allostery relay is triggered by inflammatory mediators or heterologous receptors, which generate intracellular signals that impinge on the cytoplasmic tail of the CD18 subunit These signals shift the integrin from a bent/closed to various degrees of active/open, extended conformations that have increased ligand binding affinity[16,17]. Recent studies show that FcγR-IgG interactions are regulated by the IgG subclass composition and by the glycan structure of the Fc region wherein IgG sialylation reduces FcγR affinity[1]
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