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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01200/full |
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doaj-5f357b377b4941258e1df49800081eab |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Yebin Zhou Bo Chen Nanette Mittereder Raghothama Chaerkady Martin Strain Ling-Ling An Saifur Rahman Wenting Ma Choon Pei Low Denice Chan Frances Neal Clifton O. Bingham Kevon Sampson Erika Darrah Richard M. Siegel Sarfaraz Hasni Felipe Andrade Katherine A. Vousden Tomas Mustelin Gary P. Sims |
| spellingShingle |
Yebin Zhou Bo Chen Nanette Mittereder Raghothama Chaerkady Martin Strain Ling-Ling An Saifur Rahman Wenting Ma Choon Pei Low Denice Chan Frances Neal Clifton O. Bingham Kevon Sampson Erika Darrah Richard M. Siegel Sarfaraz Hasni Felipe Andrade Katherine A. Vousden Tomas Mustelin Gary P. Sims Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by Neutrophils Frontiers in Immunology neutrophil citrullination PAD2 PAD4 rheumatoid arthritis |
| author_facet |
Yebin Zhou Bo Chen Nanette Mittereder Raghothama Chaerkady Martin Strain Ling-Ling An Saifur Rahman Wenting Ma Choon Pei Low Denice Chan Frances Neal Clifton O. Bingham Kevon Sampson Erika Darrah Richard M. Siegel Sarfaraz Hasni Felipe Andrade Katherine A. Vousden Tomas Mustelin Gary P. Sims |
| author_sort |
Yebin Zhou |
| title |
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_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_sort |
spontaneous secretion of the citrullination enzyme pad2 and cell surface exposure of pad4 by neutrophils |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2017-09-01 |
| 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. |
| topic |
neutrophil citrullination PAD2 PAD4 rheumatoid arthritis |
| url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01200/full |
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doaj-5f357b377b4941258e1df49800081eab2020-11-24T23:55:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-09-01810.3389/fimmu.2017.01200298252Spontaneous Secretion of the Citrullination Enzyme PAD2 and Cell Surface Exposure of PAD4 by NeutrophilsYebin Zhou0Bo Chen1Nanette Mittereder2Raghothama Chaerkady3Martin Strain4Ling-Ling An5Saifur Rahman6Wenting Ma7Choon Pei Low8Denice Chan9Frances Neal10Clifton O. Bingham11Kevon Sampson12Erika Darrah13Richard M. Siegel14Sarfaraz Hasni15Felipe Andrade16Katherine A. Vousden17Tomas Mustelin18Gary P. Sims19Department of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesAntibody Discovery and Protein Engineering, MedImmune LLC., Gaithersburg, MD, United StatesAntibody Discovery and Protein Engineering, MedImmune LTD., Cambridge, United KingdomDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesAntibody Discovery and Protein Engineering, MedImmune LTD., Cambridge, United KingdomAntibody Discovery and Protein Engineering, MedImmune LTD., Cambridge, United KingdomAntibody Discovery and Protein Engineering, MedImmune LTD., Cambridge, United KingdomDivision of Rheumatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United StatesDivision of Rheumatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United StatesDivision of Rheumatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United StatesImmunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, United StatesOffice of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, United StatesDivision of Rheumatology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United StatesAntibody Discovery and Protein Engineering, MedImmune LTD., Cambridge, United KingdomDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesDepartment of Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, MD, United StatesAutoantibodies 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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01200/fullneutrophilcitrullinationPAD2PAD4rheumatoid arthritis |