Journal
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
Volume 378, Issue 1890, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rstb.2022.0247
Keywords
neutrophils; integrins; histones; deimination; profilin; PAD4
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The response of neutrophils to integrin engagement stimulates the activity of PAD4, leading to histone and profilin deimination, which play a crucial role in cell adhesion and chemotaxis.
Neutrophil adhesion to endothelia, entry into tissues and chemotaxis constitute essential steps in the immune response to infections that drive inflammation. Neutrophils bind to other cells and migrate via adhesion receptors, notably the alpha(M)beta(2) integrin dimer (also called Mac-1, CR3 or CD11b/CD18). Here, the response of neutrophils to integrin engagement was examined by monitoring the activity of peptidylarginine deiminase 4 (PAD4). Histone H3 deimination was strongly stimulated by manganese, an integrin-activating divalent cation, even in the absence of additional inflammatory stimuli. Manganese-induced cell attachment resulted in neutrophil swarm formation that paralleled histone deimination, whereas antibodies that impair integrin binding prevented both cell adhesion and histone deimination. Manganese treatment led to putative deimination of profilin, a protein that functions as an actin-organizing hub, as detected by two-dimensional gel electrophoresis and citrulline immunoblotting. Cl-amidine, a covalent inhibitor of PAD4, and GSK484, a specific PAD4 inhibitor, blocked profilin deimination. Neutrophil migration toward leukotriene B4 and toward synovial fluid from a rheumatoid arthritis patient were inhibited by chloramidine, thus supporting the contribution of deimination to chemotaxis. The data, based on a simplified system for integrin activation, imply a mechanism whereby integrin attachment coordinates neutrophil responses to inflammation and orchestrates deimination of nuclear and cytoskeletal proteins.This article is part of the Theo Murphy meeting issue 'The virtues and vices of protein citrullination'.
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