Inhibitory affinity modulation of FcγRIIA ligand binding by glycosphingolipids by inside-out signaling.

Autor:	Okubo K; Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA., Brenner MD; Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA., Cullere X; Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA., Saggu G; Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA., Patchen ML; Immuno Research, Inc., Eagan, MN 55121, USA., Bose N; Biothera Pharmaceuticals, Inc., Eagan, Minnesota, MN 55121, USA., Mihori S; Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA., Yuan Z; Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA., Lowell CA; Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA., Zhu C; Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332, USA., Mayadas TN; Department of Pathology, Brigham and Women's Hospital & Harvard Medical School, Boston, MA 02115, USA. Electronic address: tmayadas@rics.bwh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 May 18; Vol. 35 (7), pp. 109142.
DOI:	10.1016/j.celrep.2021.109142
Abstrakt:	The interaction of the human FcγRIIA with immune complexes (ICs) promotes neutrophil activation and thus must be tightly controlled to avoid damage to healthy tissue. Here, we demonstrate that a fungal-derived soluble β-1,3/1,6-glucan binds to the glycosphingolipid long-chain lactosylceramide (LacCer) to reduce FcγRIIA-mediated recruitment to immobilized ICs under flow, a process requiring high-affinity FcγRIIA-immunoglobulin G (IgG) interactions. The inhibition requires Lyn phosphorylation of SHP-1 phosphatase and the FcγRIIA immunotyrosine-activating motif. β-glucan reduces the effective 2D affinity of FcγRIIA for IgG via Lyn and SHP-1 and, in vivo, inhibits FcγRIIA-mediated neutrophil recruitment to intravascular IgG deposited in the kidney glomeruli in a glycosphingolipid- and Lyn-dependent manner. In contrast, β-glucan did not affect FcγR functions that bypass FcγR affinity for IgG. In summary, we have identified a pathway for modulating the 2D affinity of FcγRIIA for ligand that relies on LacCer-Lyn-SHP-1-mediated inhibitory signaling triggered by β-glucan, a previously described activator of innate immunity. Competing Interests: Declaration of interests M.L.P. owns stock/stock options in Biothera Pharmaceuticals, Inc. and is employed by Immuno Research, Inc. N.B. is employed by and own stock/stock options in Biothera Pharmaceuticals, Inc. The remaining authors have no conflicts of interest to disclose. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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