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

Gurpanna Saggu, Koshu Okubo, Yunfeng Chen, Ravi Vattepu, Naotake Tsuboi, Florencia Rosetti, Xavier Cullere, Nathaniel Washburn, Suhail Tahir, Aaron M. Rosado, Steven M. Holland, Robert M. Anthony, Mehmet Sen, Cheng Zhu and Tanya N. Mayadas ()
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Gurpanna Saggu: Brigham and Women’s Hospital & Harvard Medical School
Koshu Okubo: Brigham and Women’s Hospital & Harvard Medical School
Yunfeng Chen: Georgia Institute of Technology
Ravi Vattepu: Massachusetts General Hospital & Harvard Medical School
Naotake Tsuboi: Brigham and Women’s Hospital & Harvard Medical School
Florencia Rosetti: Brigham and Women’s Hospital & Harvard Medical School
Xavier Cullere: Brigham and Women’s Hospital & Harvard Medical School
Nathaniel Washburn: Momenta Pharmaceuticals
Suhail Tahir: Brigham and Women’s Hospital & Harvard Medical School
Aaron M. Rosado: Georgia Institute of Technology
Steven M. Holland: National Institutes of Health
Robert M. Anthony: Massachusetts General Hospital & Harvard Medical School
Mehmet Sen: University of Houston
Cheng Zhu: Georgia Institute of Technology
Tanya N. Mayadas: Brigham and Women’s Hospital & Harvard Medical School

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07506-1

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