Cis interaction between sialylated FcγRIIA and the αI-domain of Mac-1 limits antibody-mediated neutrophil recruitment
Year: 2018
Type: article
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.
Source: Nature Communications
Institutions: Brigham and Women's Hospital, Harvard University, Georgia Institute of Technology, Massachusetts General Hospital, Fujita Health University, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Momenta Pharmaceuticals (United States), National Institutes of Health, National Institute of Allergy and Infectious Diseases, University of Houston
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Cleveland Clinic, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources
Awards: G3390456240, The atomic basis of leukocyte adhesion receptor (CD11c/CD18) activation and antagonism in solution, Generation and Characterization of Mice with Tissue Specific Expression of Lupus Risk ITGAM SNPs, TNFR2 Regulation of Leukocyte Recruitment in Glomerulonephritis, G4704709168, G620462146, G6468115476, G750164431, T cell compartmentalization and antiviral response, Regulators of immune complex mediated neutrophil antigen presentation
OpenAlex ID: W2901515600