Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients
Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Alth...
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| Format: | Article |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1084283/full |
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| author | Minjie Xu Rong Du Wenping Xing Xueting Chen Jian Wan Shengqing Wang Li Xiong Kutty Selva Nandakumar Rikard Holmdahl Hui Geng |
| author_facet | Minjie Xu Rong Du Wenping Xing Xueting Chen Jian Wan Shengqing Wang Li Xiong Kutty Selva Nandakumar Rikard Holmdahl Hui Geng |
| author_sort | Minjie Xu |
| collection | DOAJ |
| description | Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA. |
| first_indexed | 2024-04-10T20:46:14Z |
| format | Article |
| id | doaj.art-beda157e5b934232b808e9ed957c18f0 |
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| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T20:46:14Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-beda157e5b934232b808e9ed957c18f02023-01-24T07:55:24ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011410.3389/fimmu.2023.10842831084283Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patientsMinjie Xu0Rong Du1Wenping Xing2Xueting Chen3Jian Wan4Shengqing Wang5Li Xiong6Kutty Selva Nandakumar7Rikard Holmdahl8Hui Geng9Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaDepartment of Rheumatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, ChinaHubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaHubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaHubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaDepartment of Dermatology, Hospital affiliated to Central China Normal University, Wuhan, ChinaHubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaDepartment of Environmental and Biosciences, School of Business, Innovation and Sustainability, Halmstad University, Halmstad, SwedenDivision of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, SwedenHubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, ChinaCitrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1084283/fullrheumatoid arthritiscitrullinationplateletsanti-citrullinated protein antibodies (ACPA)platelet derived microparticles (PDP) |
| spellingShingle | Minjie Xu Rong Du Wenping Xing Xueting Chen Jian Wan Shengqing Wang Li Xiong Kutty Selva Nandakumar Rikard Holmdahl Hui Geng Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients Frontiers in Immunology rheumatoid arthritis citrullination platelets anti-citrullinated protein antibodies (ACPA) platelet derived microparticles (PDP) |
| title | Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients |
| title_full | Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients |
| title_fullStr | Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients |
| title_full_unstemmed | Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients |
| title_short | Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients |
| title_sort | platelets derived citrullinated proteins and microparticles are potential autoantibodies acpa targets in ra patients |
| topic | rheumatoid arthritis citrullination platelets anti-citrullinated protein antibodies (ACPA) platelet derived microparticles (PDP) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1084283/full |
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