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Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils

Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA), and elevated levels of protein citrullination can be found in the joints of patients with RA. Calcium-dependent peptidyl-arginine deiminases (PAD) are the enzymes responsible for ci...

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Autores principales: Zhou, Yebin, Chen, Bo, Mittereder, Nanette, Chaerkady, Raghothama, Strain, Martin, An, Ling-Ling, Rahman, Saifur, Ma, Wenting, Low, Choon Pei, Chan, Denice, Neal, Frances, Bingham, Clifton O., Sampson, Kevon, Darrah, Erika, Siegel, Richard M., Hasni, Sarfaraz, Andrade, Felipe, Vousden, Katherine A., Mustelin, Tomas, Sims, Gary P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622307/
https://www.ncbi.nlm.nih.gov/pubmed/28993780
http://dx.doi.org/10.3389/fimmu.2017.01200
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author Zhou, Yebin
Chen, Bo
Mittereder, Nanette
Chaerkady, Raghothama
Strain, Martin
An, Ling-Ling
Rahman, Saifur
Ma, Wenting
Low, Choon Pei
Chan, Denice
Neal, Frances
Bingham, Clifton O.
Sampson, Kevon
Darrah, Erika
Siegel, Richard M.
Hasni, Sarfaraz
Andrade, Felipe
Vousden, Katherine A.
Mustelin, Tomas
Sims, Gary P.
author_facet Zhou, Yebin
Chen, Bo
Mittereder, Nanette
Chaerkady, Raghothama
Strain, Martin
An, Ling-Ling
Rahman, Saifur
Ma, Wenting
Low, Choon Pei
Chan, Denice
Neal, Frances
Bingham, Clifton O.
Sampson, Kevon
Darrah, Erika
Siegel, Richard M.
Hasni, Sarfaraz
Andrade, Felipe
Vousden, Katherine A.
Mustelin, Tomas
Sims, Gary P.
author_sort Zhou, Yebin
collection PubMed
description Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA), and elevated levels of protein citrullination can be found in the joints of patients with RA. Calcium-dependent peptidyl-arginine deiminases (PAD) are the enzymes responsible for citrullination. PAD2 and PAD4 are enriched in neutrophils and likely drive citrullination under inflammatory conditions. PADs may be released during NETosis or cell death, but the mechanisms responsible for PAD activity under physiological conditions have not been fully elucidated. To understand how PADs citrullinate extracellular proteins, we investigated the cellular localization and activity of PAD2 and PAD4, and we report that viable neutrophils from healthy donors have active PAD4 exposed on their surface and spontaneously secrete PAD2. Neutrophil activation by some stimulatory agents increased the levels of immunoreactive PAD4 on the cell surface, and some stimuli reduced PAD2 secretion. Our data indicate that live neutrophils have the inherent capacity to express active extracellular PADs. These novel pathways are distinguished from intracellular PAD activation during NETosis and calcium influx-mediated hypercitrullination. Our study implies that extracellular PADs may have a physiological role under non-pathogenic conditions as well as a pathological role in RA.
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spelling pubmed-56223072017-10-09 Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils Zhou, Yebin Chen, Bo Mittereder, Nanette Chaerkady, Raghothama Strain, Martin An, Ling-Ling Rahman, Saifur Ma, Wenting Low, Choon Pei Chan, Denice Neal, Frances Bingham, Clifton O. Sampson, Kevon Darrah, Erika Siegel, Richard M. Hasni, Sarfaraz Andrade, Felipe Vousden, Katherine A. Mustelin, Tomas Sims, Gary P. Front Immunol Immunology Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA), and elevated levels of protein citrullination can be found in the joints of patients with RA. Calcium-dependent peptidyl-arginine deiminases (PAD) are the enzymes responsible for citrullination. PAD2 and PAD4 are enriched in neutrophils and likely drive citrullination under inflammatory conditions. PADs may be released during NETosis or cell death, but the mechanisms responsible for PAD activity under physiological conditions have not been fully elucidated. To understand how PADs citrullinate extracellular proteins, we investigated the cellular localization and activity of PAD2 and PAD4, and we report that viable neutrophils from healthy donors have active PAD4 exposed on their surface and spontaneously secrete PAD2. Neutrophil activation by some stimulatory agents increased the levels of immunoreactive PAD4 on the cell surface, and some stimuli reduced PAD2 secretion. Our data indicate that live neutrophils have the inherent capacity to express active extracellular PADs. These novel pathways are distinguished from intracellular PAD activation during NETosis and calcium influx-mediated hypercitrullination. Our study implies that extracellular PADs may have a physiological role under non-pathogenic conditions as well as a pathological role in RA. Frontiers Media S.A. 2017-09-25 /pmc/articles/PMC5622307/ /pubmed/28993780 http://dx.doi.org/10.3389/fimmu.2017.01200 Text en Copyright © 2017 Zhou, Chen, Mittereder, Chaerkady, Strain, An, Rahman, Ma, Low, Chan, Neal, Bingham, Sampson, Darrah, Siegel, Hasni, Andrade, Vousden, Mustelin and Sims. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhou, Yebin
Chen, Bo
Mittereder, Nanette
Chaerkady, Raghothama
Strain, Martin
An, Ling-Ling
Rahman, Saifur
Ma, Wenting
Low, Choon Pei
Chan, Denice
Neal, Frances
Bingham, Clifton O.
Sampson, Kevon
Darrah, Erika
Siegel, Richard M.
Hasni, Sarfaraz
Andrade, Felipe
Vousden, Katherine A.
Mustelin, Tomas
Sims, Gary P.
Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title_full Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title_fullStr Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title_full_unstemmed Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title_short Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils
title_sort spontaneous secretion of the citrullination enzyme pad2 and cell surface exposure of pad4 by neutrophils
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622307/
https://www.ncbi.nlm.nih.gov/pubmed/28993780
http://dx.doi.org/10.3389/fimmu.2017.01200
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