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Seledtsov VI, Pyshenko AA, Lyubavskaya TY, Seledtsova IA, von Delwig AA. Blood Coagulation Favors Anti-Inflammatory Immune Responses in Whole Blood. Hematol Rep 2025; 17:19. [PMID: 40277843 PMCID: PMC12026462 DOI: 10.3390/hematolrep17020019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/25/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND We studied the effects of human blood coagulation on antioxidant activity and the cellular secretion of immunoregulatory molecules in vitro. METHODS Reactive oxygen species (ROS) activity and cytokine content were determined in plasma and serum blood samples incubated with lipopolysaccharide (LPS) for 3 h or 18 h. RESULTS Coagulation process significantly decreased ROS activity induced by LPS in blood samples from healthy donors. Human serum was found to have significantly higher antioxidant activity than plasma. Blood coagulation markedly reduced LPS-induced secretion of TNF-α by cells, without significantly affecting the secretion of interleukin-1 (IL-1), IL-6, IL-8, or C-reactive protein (CRP). Blood clotting led to an increase in LPS-induced release of vascular endothelial growth factor (VEGF) by blood cells. A significant increase in procalcitonin levels was also observed in serum samples. CONCLUSIONS Blood clotting enhances the antioxidant and anti-inflammatory functions of immunoreactive blood cells.
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Affiliation(s)
- Victor I. Seledtsov
- Federal State Budgetary Scientific Institution, Russian Scientific Center for Surgery Named after Academician B.V. Petrovsky, 119991 Moscow, Russia; (A.A.P.); (T.Y.L.); (I.A.S.); (A.A.v.D.)
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Qi N, Lyu Z, Huang L, Zhao Y, Zhang W, Zhou X, Zhang Y, Cui J. Investigating the dual causative pathways linking immune cells and venous thromboembolism via Mendelian randomization analysis. Thromb J 2025; 23:8. [PMID: 39849535 PMCID: PMC11756130 DOI: 10.1186/s12959-025-00692-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/17/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) is a common vascular disease with a significant global burden, influenced by multiple factors, such as genetic, environmental, and immune components. Immune responses and shifts in immune cell profiles are closely linked to the development and progression of VTE, yet current studies are limited by confounding factors and reverse causation. To address these limitations, this study uses Mendelian randomization to explore the causal relationship between immune cell traits and VTE, aiming to provide insights into underlying mechanisms. METHODS We utilized GWAS data on 731 immunological traits (n = 3757) from the IEU OpenGWAS project and VTE (21021 cases, 391160 controls) from Finngen public data. Five commonly used Mendelian randomization (MR) methods were employed, including inverse-variance weighted (IVW), MR-Egger regression, weighted median estimator (WME), and both weighted and simple models to analyze their associations. Sensitivity checks for the results included pleiotropy tests, heterogeneity tests, and leave-one-out analyses. RESULTS From a strictly statistical perspective, no significant associations were observed after FDR correction. However, our exploratory analysis suggested potential trends between immune cell traits and VTE. When immune cells were considered as the exposure and VTE as the outcome, 44 immune cell traits were suggestively associated with VTE based on uncorrected p-values. Conversely, when VTE was considered as the exposure, it appeared to influence immune cell traits. Specifically, secreting CD4 regulatory T cells (OR = 0.9084; 95% CI: 0.8418-0.9804; P = 0.0135; FDR = 0.7339) and activated and resting CD4 regulatory T cells (OR = 0.9275; 95% CI: 0.8622-0.9977; P = 0.0433; FDR = 0.8048) suggested a potential protective trend against VTE. On the other hand, B cells expressing CD20 (OR = 1.0697; 95% CI: 1.0227-1.1188; P = 0.0033; FDR = 0.5767) and myeloid cells expressing CD33 (OR = 1.0199; 95% CI: 1.0021-1.0382; P = 0.0296; FDR = 0.7339) may be linked to an increased risk of VTE. CONCLUSIONS From a strict statistical perspective, no significant associations were identified after FDR correction. However, our analysis using MR method suggests a potential link between VTE and immune cell traits, suggesting the complex interplay between the immune system and thrombotic events. While this study is exploratory and needs validation, the findings of this study are hypothesis-generating with resect to the mechanisms underlying VTE and encourage further investigation into the role of immune activity in VTE pathology.
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Affiliation(s)
- Ning Qi
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Zhuochen Lyu
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Lu Huang
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Yun Zhao
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Wan Zhang
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Xinfeng Zhou
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Yang Zhang
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Jiasen Cui
- Department of Vascular Surgery, Huadong Hospital, Fudan University, Shanghai, 200040, China.
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, 200040, China.
- Department of Vascular Surgery and Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, 221 West Yan'an Road, Jing'an District, Shanghai, 200040, China.
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Kumar V, Stewart Iv JH. Platelet's plea to Immunologists: Please do not forget me. Int Immunopharmacol 2024; 143:113599. [PMID: 39547015 DOI: 10.1016/j.intimp.2024.113599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/07/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
Platelets are non-nucleated mammalian cells originating from the cytoplasmic expulsion of the megakaryocytes. Megakaryocytes develop during hematopoiesis through megakaryopoiesis, whereas platelets develop from megakaryocytes through thrombopoiesis. Since their first discovery, platelets have been studied as critical cells controlling hemostasis or blood coagulation. However, coagulation and innate immune response are evolutionarily linked processes. Therefore, it has become critical to investigate the immunological functions of platelets to maintain immune homeostasis. Advances in immunology and platelet biology research have explored different critical roles of platelets, including phagocytosis, release of different immune mediators, and controlling functions of different immune cells by direct interaction and immune mediators. The current article discusses platelet's development and their critical role as innate immune cells, which express different pattern recognition receptors (PRRs), recognizing different pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and death/damage-associated molecular patterns (DAMPs) and their direct interactions with innate and adaptive immune cells to maintain immune homeostasis.
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Affiliation(s)
- Vijay Kumar
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA.
| | - John H Stewart Iv
- Department of Surgery, Laboratory of Tumor Immunology and Immunotherapy, Medical Education Building-C, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310 USA
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Naghinezhad J, Hosseini E, Siavashpour Z, Houshyari M, Khajetash B, Ghasemzadeh M. Designing a linear accelerator-based "X irradiation system" for platelet products: an efficient, safe, accessible and cost-effective alternative for conventional X- or gamma irradiators. Sci Rep 2024; 14:28363. [PMID: 39550453 PMCID: PMC11569130 DOI: 10.1038/s41598-024-80118-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/14/2024] [Indexed: 11/18/2024] Open
Abstract
X-irradiation of blood products is an alternative for gamma-ray to prevent post-transfusion GvHD. However, commercial X-irradiators are not widely available while little is known about their safety and efficacy for platelet products. This study introduces an efficient, accessible and cost-effective "X irradiation system" for platelet concentrates (PCs). By constructing a suitable radiation box (phantom) for a clinically available linear accelerator, an "X irradiation system" was designed specifically for PCs. PCs were divided into three equal bags either exposed to X- and gamma-irradiation or kept unirradiated (control). Irradiation-induced inhibition of T cells proliferation was examined by MTT and cell cycle assays on mononuclear cells (MNCs) obtained from PCs. The inhibitory effect of irradiation on allorecognition ability of MNCs was assessed by mixed lymphocyte reaction where MTT evaluated lymphocyte proliferation responses and flowcytometry examined CD8+T lymphocytes activity. Platelet activation was also examined with P-selectin expression and PAC-1 binding by flowcytometry. X- and gamma-irradiation reduced T cell proliferation while disturbing the cell-cycle with reduced entry of T-cells into the S phase and their G2 arrest. Both types of irradiations also effectively reduced "lymphocyte allorecognition responses" while inactivating CD8+T lymphocytes in platelet products but with no significant effect on platelet activity. This is the first study that showed "X irradiation system" effectively suppresses T cell proliferation and CD8+T lymphocyte activity in platelet products, with no effect to platelet quality and activation markers. This may suggest the LINAC-based "X irradiation system" with a dose of 30Gy as efficient and safe as gamma-irradiation for platelet products.
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Affiliation(s)
- Jalal Naghinezhad
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran
| | - Ehteramolsadat Hosseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran.
| | - Zahra Siavashpour
- Radiology oncology Department, Medical School, Shohada-e Tajrish Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Houshyari
- Radiology oncology Department, Medical School, Shohada-e Tajrish Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Benyamin Khajetash
- Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Ghasemzadeh
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization Building, Next to the Milad Tower, Hemmat Exp. Way, P.O.Box:14665-1157, Tehran, Iran.
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5
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Wang L, Wang H, Zhu M, Ni X, Sun L, Wang W, Xie J, Li Y, Xu Y, Wang R, Han S, Zhang P, Peng J, Hou M, Hou Y. Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia. Blood 2024; 144:99-112. [PMID: 38574321 DOI: 10.1182/blood.2023022738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/11/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
ABSTRACT Platelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA-corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.
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Affiliation(s)
- Lingjun Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Haoyi Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Mingfang Zhu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Xiaofei Ni
- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Lu Sun
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Wanru Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Jie Xie
- Department of Hematology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yubin Li
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Yitong Xu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ruting Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Shouqing Han
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ping Zhang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Yu Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
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Tuerhong N, Yang Y, Wang C, Huang P, Li Q. Interactions between platelets and the cancer immune microenvironment. Crit Rev Oncol Hematol 2024; 199:104380. [PMID: 38718939 DOI: 10.1016/j.critrevonc.2024.104380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 06/16/2024] Open
Abstract
Cancer is a leading cause of death in both China and developed countries due to its high incidence and low cure rate. Immune function is closely linked to the development and progression of tumors. Platelets, which are primarily known for their role in hemostasis, also play a crucial part in the spread and progression of tumors through their interaction with the immune microenvironment. The impact of platelets on tumor growth and metastasis depends on the type of cancer and treatment method used. This article provides an overview of the relationship between platelets and the immune microenvironment, highlighting how platelets can either protect or harm the immune response and cancer immune escape. We also explore the potential of available platelet-targeting strategies for tumor immunotherapy, as well as the promise of new platelet-targeted tumor therapy methods through further research.
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Affiliation(s)
- Nuerye Tuerhong
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Yang Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Chenyu Wang
- The Second Clinical Medical College, Lanzhou university, No. 222 South Tianshui Road, Gansu, China
| | - Peng Huang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China
| | - Qiu Li
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China; West China Biomedical Big Data Center, Sichuan University, No. 37, GuoXue Xiang Chengdu, Sichuan, China.
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7
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Abdelfattah A, Hijjawi NS, Jacoub K. An overview of qualitative and quantitative platelet abnormalities in schistosomiasis. Parasitol Res 2024; 123:225. [PMID: 38809265 DOI: 10.1007/s00436-024-08245-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Schistosomiasis is a neglected tropical disease referring to the infection with blood parasitic trematodes of the genus Schistosoma. It impacts millions of people worldwide, primarily in low-to-middle-income countries. Patients infected with schistosomiasis often exhibit a distinct hematological profile, including anemia, eosinophilia, thrombocytopenia, and coagulopathy. Platelets, essential components of the hemostatic system, play a crucial role in the pathogenesis of schistosomiasis. Schistosomes secrete serine proteases and express ectoenzymes, such as calpain protease, alkaline phosphatase (SmAP), phosphodiesterase (SmNPP5), ATP diphosphohydrolase (SmATPDase1), serine protease Sk1, SmSP2, and Sm22.6, which can interfere with platelet normal functioning. This report provides comprehensive, up-to-date information on platelet abnormalities observed in patients with schistosomiasis, highlighting their importance in the disease progression and complications. It delves into the interactions between platelets and schistosomes, including the impact of platelet dysfunction on hemostasis and immune responses, immune-mediated platelet destruction, and the potential mechanisms by which schistosome tegumental ectoenzymes affect platelets. Furthermore, the report clarifies the relationship between platelet abnormalities and clinical manifestations such as thrombocytopenia, coagulation disorders, and the emergence of portal hypertension and gastrointestinal bleeding. Understanding the complex interplay between platelets and schistosomes is crucial for improving patient management and outcomes in schistosomiasis, particularly for those with platelet alterations. This knowledge contributes to improved diagnostic methods, innovative treatment strategies, and global efforts to control and eliminate schistosomiasis.
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Affiliation(s)
- Ali Abdelfattah
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan.
| | - Nawal S Hijjawi
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan
| | - Khaldun Jacoub
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, The Hashemite University, Zarqa, 13133, Jordan
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8
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Nicolai L, Pekayvaz K, Massberg S. Platelets: Orchestrators of immunity in host defense and beyond. Immunity 2024; 57:957-972. [PMID: 38749398 DOI: 10.1016/j.immuni.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 04/06/2024] [Accepted: 04/12/2024] [Indexed: 06/05/2024]
Abstract
Platelets prevent blood loss during vascular injury and contribute to thrombus formation in cardiovascular disease. Beyond these classical roles, platelets are critical for the host immune response. They guard the vasculature against pathogens via specialized receptors, intracellular signaling cascades, and effector functions. Platelets also skew inflammatory responses by instructing innate immune cells, support adaptive immunosurveillance, and influence antibody production and T cell polarization. Concomitantly, platelets contribute to tissue reconstitution and maintain vascular function after inflammatory challenges. However, dysregulated activation of these multitalented cells exacerbates immunopathology with ensuing microvascular clotting, excessive inflammation, and elevated risk of macrovascular thrombosis. This dichotomy underscores the critical importance of precisely defining and potentially modulating platelet function in immunity.
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Affiliation(s)
- Leo Nicolai
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
| | - Kami Pekayvaz
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Steffen Massberg
- Medizinische Klinik und Poliklinik I, University Hospital Ludwig-Maximilian University, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
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9
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Wang B, Wang Z, Yang W, Han L, Huang Q, Yawalkar N, Zhang Z, Yao Y, Yan K. Unlocking the role of the B7-H4 polymorphism in psoriasis: Insights into methotrexate treatment outcomes: A prospective cohort study. Immunology 2024; 171:104-116. [PMID: 37814391 DOI: 10.1111/imm.13704] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/28/2023] [Indexed: 10/11/2023] Open
Abstract
B7-H4 is a recently discovered member of B7 family that negatively regulates T-cell immunity, specifically Th1 and Th17 cell responses. However, its role in the pathogenesis of psoriasis has yet to be determined. This study aims to investigate the effect of B7-H4 polymorphism on the efficacy of methotrexate (MTX) and its mechanism in psoriasis. Four single nucleotide polymorphisms of B7-H4 were genotyped in 310 psoriatic patients who received 12-week MTX. The protein expression of B7-H4 in platelets was characterized using immunofluorescence staining, confocal laser scanning microscopy, and flow cytometry techniques. We found that GG genotype carriers of B7-H4 rs1935780 had a lower Psoriasis Area and Severity Index (PASI) 75 response rate and higher weight (p = 0.0245) and body mass index (p = 0.0185) than AA and AG genotype carriers. Multiple regression analysis showed that the PASI score at baseline (p = 0.01) and age at disease onset (p = 0.003) were positively correlated with PASI 75 response rate, while weight (p = 0.005) and the rs1935780 genotype (p = 0.003) were negatively associated with PASI 75 response rate. B7-H4 was expressed in the platelet plasma membrane and cytoplasm. Furthermore, the expression of B7-H4 protein in platelets was lower in good responders than in non-responders and was upregulated considerably after 12-week MTX or in vitro MTX stimulation in good responders. Collectively, these results demonstrate that psoriatic patients with GG genotype of B7-H4 rs1935780 had a poorer response to MTX. Low expression of B7-H4 protein in platelets correlated with better clinical outcomes of MTX in psoriasis.
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Affiliation(s)
- Bing Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Zhicheng Wang
- Department of Transfusion Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Wenjing Yang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Ling Han
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Qiong Huang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Nikhil Yawalkar
- Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Zhenghua Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
| | - Yu Yao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Kexiang Yan
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai Institute of Dermatology, Shanghai, China
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Dharmapuri S, Özbek U, Jethra H, Jun T, Marron TU, Saeed A, Huang YH, Muzaffar M, Pinter M, Balcar L, Fulgenzi C, Amara S, Weinmann A, Personeni N, Scheiner B, Pressiani T, Navaid M, Bengsch B, Paul S, Khan U, Bettinger D, Nishida N, Mohamed YI, Vogel A, Gampa A, Korolewicz J, Cammarota A, Kaseb A, Galle PR, Pillai A, Wang YH, Cortellini A, Kudo M, D’Alessio A, Rimassa L, Pinato DJ, Ang C. Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma. World J Gastrointest Oncol 2023; 15:1900-1912. [PMID: 38077640 PMCID: PMC10701235 DOI: 10.4251/wjgo.v15.i11.1900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 09/14/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND A well-recognized class effect of immune checkpoint inhibitors (ICI) is immune-related adverse events (IrAEs) ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI. Deaths are reported in < 5% of patients treated with ICI. There are, however, no reliable markers to predict the onset and severity of IrAEs. We tested the association between neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) at baseline with development of clinically significant IrAEs (grade ≥ 2) in hepatocellular carcinoma (HCC) patients treated with ICI. AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs (grade ≥ 2) in HCC patients treated with ICI. METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers. NLR = absolute neutrophil count/absolute lymphocyte count (ALC) and PLR = platelet count/ALC. Cutoff of 5 was used for NLR and 300 for PLR based on literature. We also tested the association between antibiotic and steroid exposure to IrAEs. RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States (67%), Asia (14%) and Europe (19%). Most patients received Nivolumab (n = 255, 71%). One hundred sixty-seven (46%) patients developed at least one IrAE, highest grade 1 in 80 (48%), grade ≥ 2 in 87 (52%) patients. In a univariable regression model PLR > 300 was significantly associated with a lower incidence of grade ≥ 2 IrAEs (OR = 0.40; P = 0.044). Similarly, a trend was observed between NLR > 5 and lower incidence of grade ≥ 2 IrAEs (OR = 0.58; P = 0.097). Multivariate analyses confirmed PLR > 300 as an independent predictive marker of grade ≥ 2 IrAEs (OR = 0.26; P = 0.011), in addition to treatment with programmed cell death ligand 1 (PD-1)/cytotoxic T lymphocyte-associated protein-4 (OR = 2.57; P = 0.037) and PD-1/tyrosine kinase inhibitor (OR = 3.39; P = 0.01) combinations. Antibiotic use was not associated with IrAE incidence (OR = 1.02; P = 0.954). Patients treated with steroids had a > 2-fold higher incidence of grade ≥ 2 IrAEs (OR = 2.74; P < 0.001), although 74% were prescribed steroids for the treatment of IrAEs. CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs, lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI. This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.
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Affiliation(s)
- Sirish Dharmapuri
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Umut Özbek
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Hiren Jethra
- Department of Data Analytics Harrisburg, Harrisburg University of Science and Technology, Harrisburd, PA 17101, United States
| | - Tomi Jun
- SEMA4, Stamford, CT 06902, United States
| | - Thomas U Marron
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
| | - Anwaar Saeed
- Division of Medical Oncology Kansas, University of Kansas Cancer Center, Kansas, MO 66160, United States
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Mahvish Muzaffar
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States
| | - Matthias Pinter
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Lorenz Balcar
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Claudia Fulgenzi
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
| | - Suneetha Amara
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States
| | - Arndt Weinmann
- Department of Hepatology, Johannes Gutenberg-University Medical Centre, Niedersachsen 30625, Germany
| | - Nicola Personeni
- Medical Oncology Unit, ASST Garda, Via Lungomella Valsecchi, Brescia, Manerbio 25025, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano 20089, Italy
| | - Bernhard Scheiner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano 20089, Italy
| | - Musharraf Navaid
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27858, United States
| | - Bertram Bengsch
- Department of Medicine II, Univ Med Ctr Freiburg, Hugstetter Str 55, University Hospital Freiburg, Freiburg D-79106, Germany
| | - Sonal Paul
- Department of Oncology Baltimore, LifeBridge Health, Baltimore, MD 21215, United States
| | - Uqba Khan
- Division of Hematology and Oncology, Weill Cornell Medical College, NY 10065, United States
| | - Dominik Bettinger
- Department of Medicine II, Univ Med Ctr Freiburg, Hugstetter Str 55, University Hospital Freiburg, Freiburg D-79106, Germany
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 577-8502, Japan
| | - Yehia Ibrahim Mohamed
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Arndt Vogel
- Department of Gastroenterology Hepatology and Endocrinology, HannoverArndt Vogel, Medical School Hannover, Carl-Neubergstr., Hannover 30659, Germany
| | - Anuhya Gampa
- Department of Hepatology, Rush University Medical Group 1725 W Harrison St Ste 158, Chicago, IL 60612, United States
| | - James Korolewicz
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
| | - Antonella Cammarota
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano 20089, Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20072, Italy
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Peter R Galle
- Department of Internal Medicine I and Cirrhosis Center Mainz, University Medical Center Mainz, Johannes Gutenberg Univ Mainz, Med Klin and Poliklin, Mainz D-55131, Germany
| | - Anjana Pillai
- Department of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL 60637, United States
| | - Ying-Hong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Alessio Cortellini
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka 577-8502, Japan
| | - Antonio D’Alessio
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Milan, Rozzano 20089, Italy
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Milan, Pieve Emanuele 20072, Italy
| | - David James Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital London, London W12 0HS, United Kingdom
| | - Celina Ang
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
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11
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Szepanowski RD, Haupeltshofer S, Vonhof SE, Frank B, Kleinschnitz C, Casas AI. Thromboinflammatory challenges in stroke pathophysiology. Semin Immunopathol 2023:10.1007/s00281-023-00994-4. [PMID: 37273022 DOI: 10.1007/s00281-023-00994-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/27/2023] [Indexed: 06/06/2023]
Abstract
Despite years of encouraging translational research, ischemic stroke still remains as one of the highest unmet medical needs nowadays, causing a tremendous burden to health care systems worldwide. Following an ischemic insult, a complex signaling pathway emerges leading to highly interconnected thrombotic as well as neuroinflammatory signatures, the so-called thromboinflammatory cascade. Here, we thoroughly review the cell-specific and time-dependent role of different immune cell types, i.e., neutrophils, macrophages, T and B cells, as key thromboinflammatory mediators modulating the neuroinflammatory response upon stroke. Similarly, the relevance of platelets and their tight crosstalk with a variety of immune cells highlights the relevance of this cell-cell interaction during microvascular dysfunction, neovascularization, and cellular adhesion. Ultimately, we provide an up-to-date overview of therapeutic approaches mechanistically targeting thromboinflammation currently under clinical translation, especially focusing on phase I to III clinical trials.
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Affiliation(s)
- R D Szepanowski
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S Haupeltshofer
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S E Vonhof
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - B Frank
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - C Kleinschnitz
- Department of Neurology, University Hospital Essen, Essen, Germany.
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany.
| | - A I Casas
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
- Department of Pharmacology and Personalised Medicine, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands
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12
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Yuksel N, Saritas O, Yuksel E. Effect of thyroid hormone status on complete blood cell count-derived inflammatory biomarkers in patients with moderate-to-severe Graves' ophthalmopathy. Int Ophthalmol 2023:10.1007/s10792-023-02742-x. [PMID: 37209204 DOI: 10.1007/s10792-023-02742-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 05/06/2023] [Indexed: 05/22/2023]
Abstract
PURPOSE To evaluate the systemic inflammation in moderate-to-severe Graves' ophthalmopathy patients with abnormal thyroid function by using complete blood cell count-derived inflammatory biomarkers and compare to moderate-to-severe GO patients with regulated thyroid function and healthy controls. The second aim is to evaluate the relationship of complete blood cell count-derived inflammatory biomarkers with clinical findings in moderate-to-severe GO. METHODS In this retrospective study, 90 GO patients with abnormal thyroid function composed Group 1, 58 patients who had normal thyroid function for at least 3 months composed Group 2, and 50 healthy individuals composed Group 3. Demographic data, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and systemic immune-inflammatory index (SII) were evaluated. RESULTS There was no statistically significant difference between groups in terms of age, sex, and smoking habits (p > 0.05). There was a statistically significant difference in NLR (p = 0.011), MLR (p = 0.013), MPV (p < 0.001), and SII (p < 0.001) values among 3 groups. For NLR, MLR, and SII the highest values were detected in Group 1. MPV levels were higher in Group 3 than Groups 1 and 2 (p < 0.001). None of the hematological parameters were found to be a risk factor for any clinical severity findings of GO. CONCLUSION The higher levels of NLR, MLR, and SII levels may show systemic inflammation in GO patients with abnormal thyroid function, and this may have an impact on the clinical course of ophthalmopathy. These findings may suggest that cautious control of thyroid hormone levels is important in the management of GO.
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Affiliation(s)
- Nilay Yuksel
- Department of Ophthalmology, Ophthalmic Plastic Surgery Service, Ankara Bilkent City Hospital, Universiteler Mah 1604. Cadde No:9 Bilkent, Çankaya, 06800, Ankara, Turkey.
| | - Ozge Saritas
- Department of Ophthalmology, Ankara Bilkent City Hospital, Ankara, Turkey
| | - Erdem Yuksel
- Department of Ophthalmology, Medical Faculty, Kastamonu University, Kastamonu, Turkey
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13
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Abstract
COVID-19 is characterized by dysregulated thrombosis and coagulation that can increase mortality in patients. Platelets are fast responders to pathogen presence, alerting the surrounding immune cells and contributing to thrombosis and intravascular coagulation. The SARS-CoV-2 genome has been found in platelets from patients with COVID-19, and its coverage varies according to the method of detection, suggesting direct interaction of the virus with these cells. Antibodies against Spike and Nucleocapsid have confirmed this platelet-viral interaction. This review discusses the immune, prothrombotic, and procoagulant characteristics of platelets observed in patients with COVID-19. We outline the direct and indirect interaction of platelets with SARS-CoV-2, the contribution of the virus to programmed cell death pathway activation in platelets and the consequent extracellular vesicle release. We discuss platelet activation and immunothrombosis in patients with COVID-19, the effect of Spike on platelets, and possible activation of platelets by classical platelet activation triggers as well as contribution of platelets to complement activation. As COVID-19-mediated thrombosis and coagulation are still not well understood in vivo, we discuss available murine models and mouse adaptable strains.
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Affiliation(s)
- Anthony Sciaudone
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
| | - Heather Corkrey
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
| | - Fiachra Humphries
- Innate Immunity (F.H.). University of Massachusetts Chan Medical School, Worcester, MA
| | - Milka Koupenova
- Department of Medicine, Divisions of Cardiovascular Medicine (A.S., H.C., M.K.), University of Massachusetts Chan Medical School, Worcester, MA
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14
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Albayati S, Li N, Unsworth AJ, Liverani E. Platelet-lymphocyte co-culture serves as an ex vivo platform of dynamic heterotypic cross-talk. J Cell Commun Signal 2022; 16:661-675. [PMID: 35414144 PMCID: PMC9733731 DOI: 10.1007/s12079-022-00676-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 03/16/2022] [Indexed: 12/13/2022] Open
Abstract
Platelets are well known for their roles in hemostasis and thrombosis, and are increasingly recognized for their abilities to interact with white blood cells during inflammatory diseases, via secreted soluble factors as well as cell-cell contact. This interaction has been investigated in animal models and patient samples and has shown to be implicated in patient outcomes in several diseases. Platelet-leukocyte co-cultures are widely used to study platelet-leukocyte interactions ex vivo. However, there is a paucity with regard to the systematic characterization of cell activation and functional behaviors of platelets and leukocytes in these co-cultures. Hence we aimed to characterize a model of platelet-leukocyte co-culture ex vivo. Human peripheral blood mononuclear cell (PBMC) and platelets were isolated and co-cultured for 5 days at 37 °C in the presence or absence of anti-CD3/CD28 antibodies or PHA. We evaluated PF-4 secretion and p-selectin expression in platelets as markers of platelet activation. Lymphocyte activation was assessed by cell proliferation and cell population phenotyping, in addition to platelet-lymphocyte aggregation. Platelet secretion and p-selectin expression is maintained throughout the co-culture, indicating that platelets were viable and reactive over the 5 days. Similarly PBMCs were viable and maintained proliferative capacity. Finally, dynamic heterotypic conjugation between platelets and T lymphocytes was also observed throughout co-culture (with a peak at days 3 and 4) upon T lymphocyte activation. In conclusion, this in vitro model can successfully mimic the in vivo interaction between platelets and T lymphocytes, and can be used to confirm and/or support in vivo results.
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Affiliation(s)
- Samara Albayati
- Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Temple University Hospital, Philadelphia, PA, USA
| | - Nailin Li
- Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institutet, Stockholm, Sweden
| | - Amanda J Unsworth
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, John Dalton Building, Manchester, M1 5GD, UK
| | - Elisabetta Liverani
- Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Temple University Hospital, Philadelphia, PA, USA.
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, 58102, USA.
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15
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Choudhuri S, Garg NJ. Platelets, Macrophages, and Thromboinflammation in Chagas Disease. J Inflamm Res 2022; 15:5689-5706. [PMID: 36217453 PMCID: PMC9547606 DOI: 10.2147/jir.s380896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/24/2022] [Indexed: 11/23/2022] Open
Abstract
Chagas disease (CD) is a major health problem in the Americas and an emerging health problem in Europe and other nonendemic countries. Several studies have documented persistence of the protozoan parasite Trypanosoma cruzi, and oxidative and inflammatory stress are major pathogenic factor. Mural and cardiac thrombi, cardiac arrhythmias, and cardiomyopathy are major clinical features of CD. During T. cruzi infection, parasite-released factors induce endothelial dysfunction along with platelet (PLT) and immune-cell activation. PLTs have a fundamental role in maintaining hemostasis and preventing bleeding after vascular injury. Excessive activation of PLTs and coagulation cascade can result in thrombosis and thromboembolic events, which are recognized to occur in seropositive individuals in early stages of CD when clinically symptomatic heart disease is not apparent. Several host and parasite factors have been identified to signal hypercoagulability and increase the risk of ischemic stroke in early phases of CD. Further, PLT interaction with immune cells and their role in host defense against pathogens and inflammatory processes have only recently been recognized and evolving. In the context of parasitic diseases, PLTs function in directly responding to T. cruzi infection, and PLT interactions with immune cells in shaping the proinflammatory or immunoregulatory function of monocytes, macrophages, and neutrophils remains elusive. How T. cruzi infection alters systemic microenvironment conditions to influence PLT and immune-cell interactions is not understood. In this review, we discuss the current literature, and extrapolate the mechanistic situations to explain how PLT and innate immune cell (especially monocytes and macrophages) interactions might be sustaining hypercoagulability and thromboinflammation in chronic CD.
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Affiliation(s)
- Subhadip Choudhuri
- Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
| | - Nisha J Garg
- Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
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16
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Ditsch A, Hunold L, Hefele F, Greve F, Mair O, Biberthaler P, Heimann L, Hanschen M. Traumatic Brain Injury Induces a Differential Immune Response in Polytrauma Patients; Prospective Analysis of CD69 Expression on T Cells and Platelet Expansion. J Clin Med 2022; 11:jcm11185315. [PMID: 36142962 PMCID: PMC9504194 DOI: 10.3390/jcm11185315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Accidents and injuries are the leading causes of mortality in young people. CD4+ regulatory T cells (CD4+ Tregs), Th17 cells and platelets could be identified as key players in post-traumatic immunological dysfunction, which is a common cause of late mortality in trauma patients. The mechanisms of activation of these cell types and their interaction remain mostly unclear. Since CD69 is not only a leukocyte marker but has also immunoregulatory functions, we postulate a role for CD69 after trauma. The present study investigates the expression of CD69 on CD4+ Tregs and Th17 cells, as well as the posttraumatic expansion of platelets and hemostatic function. Subgroup analysis was performed to assess the differences between polytrauma patients with and without severe traumatic brain injury (TBI). Methods: In this non-interventional prospective clinical trial, we analyzed sequential blood samples over a period of 10 days from 30 patients after multiple traumas with an ISS ≥ 16. Platelet function was assessed by rotational thromboelastometry (ROTEM analysis). CD4+ Tregs and Th17 cells were stained with surface markers and analyzed by flow cytometry. Results: We were able to demonstrate a significantly increased expression of CD69 on CD4+ Tregs after trauma. Subgroup analysis revealed that the absence of severe TBI is associated with a significantly higher expression of CD69 on CD4+ Tregs and on Th17 cells. Platelets expanded and showed signs of dysfunction, while an overall tendency of posttraumatic hypercoagulation was detected. Conclusions: Our results support the concept of injury-specific immune responses and add to a further understanding of the complex pathophysiology of post-traumatic immune dysfunction.
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Affiliation(s)
- Alexander Ditsch
- Experimental Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Lea Hunold
- Experimental Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Friederike Hefele
- Experimental Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Frederik Greve
- Department of Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Olivia Mair
- Department of Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Peter Biberthaler
- Department of Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Laura Heimann
- Experimental Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
| | - Marc Hanschen
- Experimental Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
- Department of Trauma Surgery, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany
- Correspondence:
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17
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Scopelliti F, Cattani C, Dimartino V, Mirisola C, Cavani A. Platelet Derivatives and the Immunomodulation of Wound Healing. Int J Mol Sci 2022; 23:ijms23158370. [PMID: 35955503 PMCID: PMC9368989 DOI: 10.3390/ijms23158370] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 02/01/2023] Open
Abstract
Besides their primary role in hemostasis, platelets contain a plethora of immunomodulatory molecules that profoundly affect the entire process of wound repair. Therefore, platelet derivatives, such as platelet-rich plasma or platelet lysate, have been widely employed with promising results in the treatment of chronic wounds. Platelet derivatives provide growth factors, cytokines, and chemokines targeting resident and immigrated cells belonging to the innate and adaptive immune system. The recruitment and activation of neutrophils and macrophages is critical for pathogen clearance in the early phase of wound repair. The inflammatory response begins with the release of cytokines, such as TGF-β, aimed at damping excessive inflammation and promoting the regenerative phase of wound healing. Dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wound. In this review, we summarize the role of the different immune cells involved in wound healing, particularly emphasizing the function of platelet and platelet derivatives in orchestrating the immunological response.
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18
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Cui J, Li H, Chen Z, Dong T, He X, Wei Y, Li Z, Duan J, Cao T, Chen Q, Ma D, Zhou Y, Wang B, Shi M, Zhang Q, Xiong L, Qin D. Thrombo-Inflammation and Immunological Response in Ischemic Stroke: Focusing on Platelet-Tregs Interaction. Front Cell Neurosci 2022; 16:955385. [PMID: 35846566 PMCID: PMC9278516 DOI: 10.3389/fncel.2022.955385] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 06/13/2022] [Indexed: 02/05/2023] Open
Abstract
Strokes are mainly caused by thromboembolic obstruction of a major cerebral artery. Major clinical manifestations include paralysis hemiplegia, aphasia, memory, and learning disorders. In the case of ischemic stroke (IS), hyperactive platelets contribute to advancing an acute thrombotic event progression. Therefore, the principal goal of treatment is to recanalize the occluded vessel and restore cerebral blood flow by thrombolysis or mechanical thrombectomy. However, antiplatelets or thrombolytic therapy may increase the risk of bleeding. Beyond the involvement in thrombosis, platelets also contribute to the inflammatory process induced by cerebral ischemia. Platelet-mediated thrombosis and inflammation in IS lie primarily in the interaction of platelet receptors with endothelial cells and immune cells, including T-cells, monocytes/macrophages, and neutrophils. Following revascularization, intervention with conventional antiplatelet medicines such as aspirin or clopidogrel does not substantially diminish infarct development, most likely due to the limited effects on the thrombo-inflammation process. Emerging evidence has shown that T cells, especially regulatory T cells (Tregs), maintain immune homeostasis and suppress immune responses, playing a critical immunomodulatory role in ischemia-reperfusion injury. Hence, considering the deleterious effects of inflammatory and immune responses, there is an urgent need for more targeted agents to limit the thrombotic-inflammatory activity of platelets and minimize the risk of a cerebral hemorrhage. This review highlights the involvement of platelets in neuroinflammation and the evolving role of Tregs and platelets in IS. In response to all issues, preclinical and clinical strategies should generate more viable therapeutics for preventing and managing IS with immunotherapy targeting platelets and Tregs.
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Affiliation(s)
- Jieqiong Cui
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Huayan Li
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Zongning Chen
- Department of General Medicine, Lijiang People’s Hospital, Lijiang, China
| | - Ting Dong
- Department of Laboratory Medicine, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Xiying He
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Yuanyuan Wei
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
| | - Zhengkun Li
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Jinfeng Duan
- School of Chinese Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Ting Cao
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Qian Chen
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Dongmei Ma
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Yang Zhou
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Bo Wang
- The First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, China
| | - Mingqin Shi
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
| | - Qin Zhang
- Department of Laboratory Medicine, The First People’s Hospital of Yunnan Province, Kunming, China
| | - Lei Xiong
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
| | - Dongdong Qin
- School of Basic Medical Sciences, Yunnan University of Chinese Medicine, Kunming, China
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19
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Min Y, Hao L, Liu X, Tan S, Song H, Ni H, Sheng Z, Jooss N, Liu X, Malmström RE, Sun Y, Liu J, Tang H, Zhang H, Ma C, Peng J, Hou M, Li N. Platelets fine-tune effector responses of naïve CD4 + T cells via platelet factor 4-regulated transforming growth factor β signaling. Cell Mol Life Sci 2022; 79:247. [PMID: 35437611 PMCID: PMC9016031 DOI: 10.1007/s00018-022-04279-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 12/15/2022]
Abstract
Background and aim Platelets are an able regulator of CD4+ T cell immunity. Herein, the mechanisms underlying platelet-regulated effector responses of naïve CD4+ T (Tn) cells were investigated. Methods Platelet–Tn cell co-cultures of human cells, genetically modified murine models, and high-throughput bioinformatic analyses were combined to elucidate molecular mechanisms of platelet-dependent regulation. Results Platelets exerted sophisticated regulation on effector responses of type 1, 2, and 17 T helper (Th1/Th2/Th17) and regulatory T (Treg) cells, in time-, concentration-, and organ-dependent manners and with close cooperation of transforming growth factor β (TGFβ) and platelet factor 4 (PF4). PF4 at low concentrations reinforced TGFβ signaling by heteromerizing with type III TGFβ receptor (TGFBRIII), and subsequently enhanced TGFBRII expression and TGFβ signaling. High-concentration PF4 had, however, opposite effects by directly binding to TGFBRII, blocking TGFβ–TGFBRII ligation, and thus inhibiting TGFβ signaling. Furthermore, platelet depletion markedly hampered Treg and Th17 responses in the spleen but not in the lymph nodes, blockade of platelet–Tn cell contact diminished platelet effects, while spleen injection of PF4-immobilized microparticles in PF4-deficient mice mimicked platelet effects, suggesting the importance of direct platelet–Tn contact and platelet-bound PF4 for the optimal regulatory effects by platelets. Conclusion Platelets exert context-dependent regulations on effector responses of Tn cells via PF4-TGFβ duet, suggesting new possibilities of platelet-targeted interventions of T cell immunity. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04279-1.
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Affiliation(s)
- Yanan Min
- Department of Medicine-Solna, Cardiovascular Medicine Unit, J8:20, Karolinska Institute, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden.,Department of Hematology, Affiliated Hospital of Jining Medical University, Jining, China.,Department of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Long Hao
- Department of General Surgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Xinguang Liu
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Shuai Tan
- Department of Medicine-Solna, Cardiovascular Medicine Unit, J8:20, Karolinska Institute, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden
| | - Hui Song
- Department of Clinical Laboratory, Affiliated Hospital of Jining Medical University, Jining, China
| | - Hao Ni
- Department of Medicine-Solna, Cardiovascular Medicine Unit, J8:20, Karolinska Institute, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden
| | - Zi Sheng
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Natalie Jooss
- Department of Medicine-Solna, Cardiovascular Medicine Unit, J8:20, Karolinska Institute, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden
| | - Xuena Liu
- Department of Rheumatology, Qilu Hospital of Shandong University, Jinan, China
| | - Rickard E Malmström
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institute, Stockholm, Sweden.,Department of Laboratory Medicine, Clinical Pharmacology, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Yang Sun
- School of Basic Medicine, Department of Immunology and Shandong University-Karolinska Institutet Collaborative Laboratory, Shandong University Cheeloo Medical College, Jinan, China
| | - Jianguo Liu
- Shandong First Medical University and Shandong Academy of Medical Science, Institute of Immunology, Taian, China
| | - Hua Tang
- Shandong First Medical University and Shandong Academy of Medical Science, Institute of Immunology, Taian, China
| | - Hao Zhang
- Department of Hematology, Affiliated Hospital of Jining Medical University, Jining, China.,Department of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunhong Ma
- School of Basic Medicine, Department of Immunology and Shandong University-Karolinska Institutet Collaborative Laboratory, Shandong University Cheeloo Medical College, Jinan, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Nailin Li
- Department of Medicine-Solna, Cardiovascular Medicine Unit, J8:20, Karolinska Institute, Karolinska University Hospital-Solna, 171 76, Stockholm, Sweden.
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20
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La Manna MP, Orlando V, Badami GD, Tamburini B, Azgomi MS, Presti EL, Del Nonno F, Petrone L, Belmonte B, Falasca L, Carlo PD, Dieli F, Goletti D, Caccamo N. Platelets accumulate in lung lesions of tuberculosis patients and inhibit T-cell responses and Mycobacterium tuberculosis replication in macrophages. Eur J Immunol 2022; 52:784-799. [PMID: 35338775 PMCID: PMC9325462 DOI: 10.1002/eji.202149549] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/24/2021] [Accepted: 03/23/2022] [Indexed: 12/05/2022]
Abstract
Platelets regulate human inflammatory responses that lead to disease. However, the role of platelets in tuberculosis (TB) pathogenesis is still unclear. Here, we show that patients with active TB have a high number of platelets in peripheral blood and a low number of lymphocytes leading to a high platelets to lymphocytes ratio (PL ratio). Moreover, the serum concentration of different mediators promoting platelet differentiation or associated with platelet activation is increased in active TB. Immunohistochemistry analysis shows that platelets localise around the lung granuloma lesions in close contact with T lymphocytes and macrophages. Transcriptomic analysis of caseous tissue of human pulmonary TB granulomas, followed by Gene Ontology analysis, shows that 53 platelet activation‐associated genes are highly expressed compared to the normal lung tissue. In vitro activated platelets (or their supernatants) inhibit BCG‐induced T‐ lymphocyte proliferation and IFN‐γ production. Likewise, platelets inhibit the growth of intracellular macrophages of Mycobacterium (M.) tuberculosis. Soluble factors released by activated platelets mediate both immunological and M. tuberculosis replication activities. Furthermore, proteomic and neutralisation studies (by mAbs) identify TGF‐β and PF4 as the factors responsible for inhibiting T‐cell response and enhancing the mycobactericidal activity of macrophages, respectively. Altogether these results highlight the importance of platelets in TB pathogenesis.
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Affiliation(s)
- Marco P La Manna
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Valentina Orlando
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Giusto D Badami
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Bartolo Tamburini
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Mojtaba Shekarkar Azgomi
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Elena Lo Presti
- Institute for Biomedical Research and Innovation, National Research Council, Palermo, Italy
| | - Franca Del Nonno
- Pathology Unit, National Institute for Infectious Diseases L. Spallanzani-IRCCS, Rome, Italy
| | - Linda Petrone
- Translational research Unit, National Institute for Infectious Diseases L. Spallanzani-IRCCS, Rome, Italy
| | - Beatrice Belmonte
- Tumor Immunology Unit, Department of Health Science, Human Pathology Section, University of Palermo School of Medicine, Palermo, Italy
| | - Laura Falasca
- Pathology Unit, National Institute for Infectious Diseases L. Spallanzani-IRCCS, Rome, Italy
| | - Paola Di Carlo
- Department of Sciences for Health Promotion and Mother-Child Care "G. D'Alessandro", University of Palermo, Palermo, Italy
| | - Francesco Dieli
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
| | - Delia Goletti
- Translational research Unit, National Institute for Infectious Diseases L. Spallanzani-IRCCS, Rome, Italy
| | - Nadia Caccamo
- Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR).,Department of Biomedicine, Neurosciences and Advanced Diagnostic (Bi.N.D.), University of Palermo, Palermo, 90127, Italy
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21
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da Silva LQ, Silva Justo-Junior AD, Moraes Martinelli BD, da Cruz MA, Huber SC, de Lima Montalvão SA, de Freitas Filho LH, Vicente CP, Annichino-Bizzacchi JM. The role of platelet-rich plasma in the mild and severe stages of atherosclerotic disease in mice. Regen Med 2022; 17:259-270. [PMID: 35291812 DOI: 10.2217/rme-2021-0151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: Platelet-rich plasma (PRP) has a high concentration of growth factors (GFs), which present a therapeutic wound healing effect. Despite having been correlated with an immunomodulatory function, the administration of PRP has not yet been investigated in atherosclerosis models. Aim: Evaluate the effect of lyophilized PRP on atherosclerosis in mice models through serum analysis. Methods: Animals received a high-fat diet for disease induction and a weekly PRP retro-orbital application. Effectiveness was evaluated by measuring inflammatory markers in plasma following the treatment of mice with either PRP or saline solution. Results: PRP was well characterized for platelet and GF concentrations; the atherosclerotic profile was established. Cytokine concentrations were altered after PRP applications. Conclusion: PRP could modulate the inflammatory pattern in the early stages of atherosclerosis.
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Affiliation(s)
- Letícia Queiroz da Silva
- Haemostasis Laboratory, Hemocentro - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-878, Brazil
| | - Amauri da Silva Justo-Junior
- Department of Clinical Pathology, Faculty of Medical Sciences - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-970, Brazil
| | - Beatriz de Moraes Martinelli
- Haemostasis Laboratory, Hemocentro - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-878, Brazil
| | - Márcio Alves da Cruz
- Haemostasis Laboratory, Hemocentro - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-878, Brazil
| | - Stephany Cares Huber
- Haemostasis Laboratory, Hemocentro - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-878, Brazil
| | | | - Luiz Henrique de Freitas Filho
- Laboratory of Atherosclerosis, Thrombosis & Cell Therapy, Institute of Biology Pathology - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-862, Brazil
| | - Cristina Pontes Vicente
- Laboratory of Atherosclerosis, Thrombosis & Cell Therapy, Institute of Biology Pathology - State University of Campinas, UNICAMP. Campinas, São Paulo, 13083-862, Brazil
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22
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Abstract
Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for >150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.
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Affiliation(s)
- Milka Koupenova
- Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Chan Medical School, 368 Plantation Street, Worcester, MA 01605
| | - Alison Livada
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642
| | - Craig N. Morrell
- Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, NY 14642
- Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642
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23
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Bock M, Bergmann CB, Jung S, Biberthaler P, Heimann L, Hanschen M. Platelets differentially modulate CD4 + Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways. Immunol Res 2021; 70:185-196. [PMID: 34932195 PMCID: PMC8917040 DOI: 10.1007/s12026-021-09258-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/06/2021] [Indexed: 01/20/2023]
Abstract
CD4+FoxP3+ regulatory T cells (CD4+ Tregs) are known to dampen inflammation following severe trauma. Platelets were shown to augment their posttraumatic activation in burn injury, but the exact mechanisms remain unclear. We hypothesized that platelet activation mechanisms via GPIIb/IIIa, fibrinogen, and PAR4 have an immunological effect and modulate CD4+ Treg activation early after trauma. Therefore, C57Bl/6 N mice were injected with tirofiban (GPIIb/IIIa inhibition), ancrod (fibrinogen splitting enzyme), or tcY-NH2 (selective PAR4 antagonist peptide) before inducing a third-degree burn injury of 25% of the total body surface area. Changes in coagulation, and local and systemic CD4+ Treg activity were assessed via rotational thromboelastometry (ROTEM®) and phospho-flow cytometry 1 h post intervention. The inhibition of GPIIb/IIIa and fibrinogen locally led to a higher basic activity of CD4+ Tregs compared to non-inhibited animals. In contrast, PAR4 disruption on platelets locally led to an increased posttraumatic activation of CD4+ Tregs. Fibrinogen led to complete elimination of coagulation, whereas GPIIb/IIIa or PAR4 inhibition did not. GPIIb/IIIa receptor and fibrinogen inhibition increase CD4+ Tregs activity independently of trauma. Both are crucial for thrombus formation. We suggest platelets trapped in thrombi are unable to interact with CD4+ Tregs but augment their activity when circulating freely. In contrast, PAR4 seems to reduce CD4+ Treg activation following trauma. In summary, GPIIb/IIIa-, PAR4-, and fibrinogen-dependent pathways in platelets modulate CD4+ Treg baseline activity, independently from their hemostatic functionality. PAR4-dependent pathways modulate the posttraumatic interplay of platelets and CD4+ Tregs.
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Affiliation(s)
- Matthias Bock
- Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.,Department of Cardiology, School of Medicine, German Heart Centre Munich, Technical University of Munich, Lazarettstr. 36, 80636, Munich, Germany
| | - Christian B Bergmann
- Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.,Department of Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.,Division of Research, Department of Surgery, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267, USA
| | - Sonja Jung
- Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Peter Biberthaler
- Department of Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Laura Heimann
- Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany
| | - Marc Hanschen
- Experimental Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany. .,Department of Trauma Surgery, Klinikum Rechts Der Isar, School of Medicine, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany.
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24
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Figueiredo C, Blasczyk R. Generation of HLA Universal Megakaryocytes and Platelets by Genetic Engineering. Front Immunol 2021; 12:768458. [PMID: 34777386 PMCID: PMC8579098 DOI: 10.3389/fimmu.2021.768458] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Patelet transfusion refractoriness remains a relevant hurdle in the treatment of severe alloimmunized thrombocytopenic patients. Antibodies specific for the human leukocyte antigens (HLA) class I are considered the major immunological cause for PLT transfusion refractoriness. Due to the insufficient availability of HLA-matched PLTs, the development of new technologies is highly desirable to provide an adequate management of thrombocytopenia in immunized patients. Blood pharming is a promising strategy not only to generate an alternative to donor blood products, but it may offer the possibility to optimize the therapeutic effect of the produced blood cells by genetic modification. Recently, enormous technical advances in the field of in vitro production of megakaryocytes (MKs) and PLTs have been achieved by combining progresses made at different levels including identification of suitable cell sources, cell pharming technologies, bioreactors and application of genetic engineering tools. In particular, use of RNA interference, TALEN and CRISPR/Cas9 nucleases or nickases has allowed for the generation of HLA universal PLTs with the potential to survive under refractoriness conditions. Genetically engineered HLA-silenced MKs and PLTs were shown to be functional and to have the capability to survive cell- and antibody-mediated cytotoxicity using in vitro and in vivo models. This review is focused on the methods to generate in vitro genetically engineered MKs and PLTs with the capacity to evade allogeneic immune responses.
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Affiliation(s)
- Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Hannover, Germany
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25
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Page MJ, Pretorius E. Platelet Behavior Contributes to Neuropathologies: A Focus on Alzheimer's and Parkinson's Disease. Semin Thromb Hemost 2021; 48:382-404. [PMID: 34624913 DOI: 10.1055/s-0041-1733960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The functions of platelets are broad. Platelets function in hemostasis and thrombosis, inflammation and immune responses, vascular regulation, and host defense against invading pathogens, among others. These actions are achieved through the release of a wide set of coagulative, vascular, inflammatory, and other factors as well as diverse cell surface receptors involved in the same activities. As active participants in these physiological processes, platelets become involved in signaling pathways and pathological reactions that contribute to diseases that are defined by inflammation (including by pathogen-derived stimuli), vascular dysfunction, and coagulation. These diseases include Alzheimer's and Parkinson's disease, the two most common neurodegenerative diseases. Despite their unique pathological and clinical features, significant shared pathological processes exist between these two conditions, particularly relating to a central inflammatory mechanism involving both neuroinflammation and inflammation in the systemic environment, but also neurovascular dysfunction and coagulopathy, processes which also share initiation factors and receptors. This triad of dysfunction-(neuro)inflammation, neurovascular dysfunction, and hypercoagulation-illustrates the important roles platelets play in neuropathology. Although some mechanisms are understudied in Alzheimer's and Parkinson's disease, a strong case can be made for the relevance of platelets in neurodegeneration-related processes.
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Affiliation(s)
- Martin J Page
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, South Africa
| | - Etheresia Pretorius
- Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, Private Bag X1 Matieland, South Africa
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26
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Platelets, Not an Insignificant Player in Development of Allergic Asthma. Cells 2021; 10:cells10082038. [PMID: 34440807 PMCID: PMC8391764 DOI: 10.3390/cells10082038] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/26/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022] Open
Abstract
Allergic asthma is a chronic and heterogeneous pulmonary disease in which platelets can be activated in an IgE-mediated pathway and migrate to the airways via CCR3-dependent mechanism. Activated platelets secrete IL-33, Dkk-1, and 5-HT or overexpress CD40L on the cell surfaces to induce Type 2 immune response or interact with TSLP-stimulated myeloid DCs through the RANK-RANKL-dependent manner to tune the sensitization stage of allergic asthma. Additionally, platelets can mediate leukocyte infiltration into the lungs through P-selectin-mediated interaction with PSGL-1 and upregulate integrin expression in activated leukocytes. Platelets release myl9/12 protein to recruit CD4+CD69+ T cells to the inflammatory sites. Bronchoactive mediators, enzymes, and ROS released by platelets also contribute to the pathogenesis of allergic asthma. GM-CSF from platelets inhibits the eosinophil apoptosis, thus enhancing the chronic inflammatory response and tissue damage. Functional alterations in the mitochondria of platelets in allergic asthmatic lungs further confirm the role of platelets in the inflammation response. Given the extensive roles of platelets in allergic asthma, antiplatelet drugs have been tested in some allergic asthma patients. Therefore, elucidating the role of platelets in the pathogenesis of allergic asthma will provide us with new insights and lead to novel approaches in the treatment of this disease.
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27
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Tan S, Zhang J, Sun Y, Gisterå A, Sheng Z, Malmström RE, Hou M, Peng J, Ma C, Liao W, Li N. Platelets enhance CD4+ central memory T cell responses via platelet factor 4-dependent mitochondrial biogenesis and cell proliferation. Platelets 2021; 33:360-370. [PMID: 34137652 DOI: 10.1080/09537104.2021.1936479] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Platelets regulate multiple aspects of CD4+ T cell immunity, and may exert distinct regulations among different T cell subsets. Our aim was to investigate how platelets regulate CD4+ central memory T cell (Tcm) responses. αCD3/αCD28-stimulated human CD4+ Tcm cells were cultured without or with platelets or platelet-derived mediators. Polyclonal stimulation induced cell proliferation and Th1 and Treg cell activation of Tcm cells. Platelet factor 4/PF4 neutralization abolished platelet-enhanced Tcm effector responses, whilst TGFβ neutralization only partially inhibited platelet-enhanced Treg cell activation. PF4 supplementation mimicked the effects of platelet co-cultures, while PF4 receptor CXCR3 blockade and CXCR3 knockdown with siRNAs inhibited or abolished PF4-enhanced Th1 and Treg cell responses. Platelet co-cultures or PF4-treatment increased Tcm cell proliferation, whilst CXCR3 blockade counteracted. PF4-enhanced Tcm proliferation and effector cell responses were associated with mitochondrial biogenesis. Overexpression of mitochondrial transcription factor A (TFAM) mimicked PF4 effects, and PF4 treatment attenuated Akt phosphorylation of activated Tcm cells, leading to mitochondrial biogenesis. Impacts of platelets and PF4 on Tcm proliferation were further confirmed by that CXCR3 knockdown/blockade counteracted PF4-enhanced Tcm cell proliferation. In conclusion, platelets enhance Th1 and Treg cell responses of CD4+ Tcm cells, via PF4-dependent mitochondrial biogenesis and cell proliferation of Tcm cells.
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Affiliation(s)
- Shuai Tan
- Karolinska Institutet, Stockholm, Sweden.,Clinical Epidemiology Unit, Clinical Pharmacology Group, Stockholm, Sweden
| | - Junhao Zhang
- Karolinska Institutet, Stockholm, Sweden.,Clinical Epidemiology Unit, Clinical Pharmacology Group, Stockholm, Sweden.,Nanfang Hospital, Department of Oncology, Southern Medical University, Guangzhou, China
| | - Yang Sun
- Shandong University Cheeloo Medical College, School of Basic Medicine, Department of Immunology, Jinan, China
| | - Anton Gisterå
- Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Zi Sheng
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Rickard E Malmström
- Clinical Epidemiology Unit, Clinical Pharmacology Group, Stockholm, Sweden.,Department of Laboratory Medicine, Clinical Pharmacology, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Ming Hou
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Jinan, China
| | - Chunhong Ma
- Shandong University Cheeloo Medical College, School of Basic Medicine, Department of Immunology, Jinan, China
| | - Wangjun Liao
- Nanfang Hospital, Department of Oncology, Southern Medical University, Guangzhou, China
| | - Nailin Li
- Karolinska Institutet, Stockholm, Sweden.,Clinical Epidemiology Unit, Clinical Pharmacology Group, Stockholm, Sweden
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28
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Vulliamy P, Kornblith LZ, Kutcher ME, Cohen MJ, Brohi K, Neal MD. Alterations in platelet behavior after major trauma: adaptive or maladaptive? Platelets 2021; 32:295-304. [PMID: 31986948 PMCID: PMC7382983 DOI: 10.1080/09537104.2020.1718633] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/01/2020] [Accepted: 01/14/2020] [Indexed: 12/14/2022]
Abstract
Platelets are damage sentinels of the intravascular compartment, initiating and coordinating the primary response to tissue injury. Severe trauma and hemorrhage induce profound alterations in platelet behavior. During the acute post-injury phase, platelets develop a state of impaired ex vivo agonist responsiveness independent of platelet count, associated with systemic coagulopathy and mortality risk. In patients surviving the initial insult, platelets become hyper-responsive, associated with increased risk of thrombotic events. Beyond coagulation, platelets constitute part of a sterile inflammatory response to injury: both directly through release of immunomodulatory molecules, and indirectly through modifying behavior of innate leukocytes. Both procoagulant and proinflammatory aspects have implications for secondary organ injury and multiple-organ dysfunction syndromes. This review details our current understanding of adaptive and maladaptive alterations in platelet biology induced by severe trauma, mechanisms underlying these alterations, potential platelet-focused therapies, and existing knowledge gaps and their research implications.
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Affiliation(s)
- Paul Vulliamy
- Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, United Kingdom
| | - Lucy Z. Kornblith
- Department of Surgery, Zuckerberg San Francisco General Hospital and the University of California, San Francisco, San Francisco, California
| | - Matthew E. Kutcher
- Division of Trauma, Critical Care, and Acute Care Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - Mitchell J. Cohen
- Department of Surgery, University of Colorado, Aurora, Colorado
- Ernest E Moore Shock Trauma Center at Denver Health, Denver, Colorado
| | - Karim Brohi
- Centre for Trauma Sciences, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, E1 2AT, United Kingdom
| | - Matthew D. Neal
- Division of Trauma and Acute Care Surgery, Department of Surgery, University of Pittsburgh, Pittsburgh, PA
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29
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Zamora C, Cantó E, Vidal S. The Dual Role of Platelets in the Cardiovascular Risk of Chronic Inflammation. Front Immunol 2021; 12:625181. [PMID: 33868242 PMCID: PMC8046936 DOI: 10.3389/fimmu.2021.625181] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 02/15/2021] [Indexed: 11/25/2022] Open
Abstract
Patients with chronic inflammatory diseases often exhibit cardiovascular risk. This risk is associated with the systemic inflammation that persists in these patients, causing a sustained endothelial activation. Different mechanisms have been considered responsible for this systemic inflammation, among which activated platelets have been regarded as a major player. However, in recent years, the role of platelets has become controversial. Not only can this subcellular component release pro- and anti-inflammatory mediators, but it can also bind to different subsets of circulating lymphocytes, monocytes and neutrophils modulating their function in either direction. How platelets exert this dual role is not yet fully understood.
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Affiliation(s)
| | | | - Sílvia Vidal
- Inflammatory Diseases, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain
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30
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Albayati S, Vemulapalli H, Tsygankov AY, Liverani E. P2Y 12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis. J Leukoc Biol 2020; 110:141-153. [PMID: 33242353 DOI: 10.1002/jlb.3a0220-097r] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Sepsis is a complex clinical condition resulting from a serious bloodstream infection. With mortality rates as high as 50%, improved treatments are needed. Regulatory T cells (Tregs), a subset of T lymphocytes, promote the resolution of inflammation. Septic patients have elevated levels of circulating Tregs. Platelets influence the proliferation and activation of Tregs in vitro. However, modulating platelet-Tregs interaction during sepsis may restraing Treg proliferation, leading to the restoration of immunologic homeostasis. P2Y12 is a purinergic receptor present on platelets and T lymphocytes. Blocking P2Y12 improves the outcome of sepsis. We investigated whether blocking P2Y12 alters platelet-Treg interaction in vivo. We used the murine model of sepsis, cecal ligation, and puncture (CLP) and we blocked P2Y12 using the P2Y12 antagonist, clopidogrel. Twenty-four hours after surgery, we measured Treg population sizes in the spleens of the Sham, CLP, and CLP + clopidogrel groups. We investigated the effect of blocking P2Y12 in vitro using cocultures of human platelets and T cells with or without anti-CD3/CD28. P2Y12 was blocked using AR-C69931MX. Treg population sizes were reduced in the septic mice treated with clopidogrel compared with untreated septic mice. Aggregation of platelets and CD4+ T cells was reduced in treated CLP mice compared with untreated CLP mice. P2Y12 antagonism changes how platelets influence T cells in vitro, depending on T-cell activation. In conclusion, blockade of the P2Y12 signaling pathway restrains Treg proliferation in vivo and in vitro. Targeting platelets to control Treg proliferation and activity may be a promising strategy for treating sepsis.
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Affiliation(s)
- Samara Albayati
- Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, 3420 North Broad Street, Philadelphia, PA, 19140, USA
| | - Harika Vemulapalli
- Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, 3420 North Broad Street, Philadelphia, PA, 19140, USA
| | - Alexander Y Tsygankov
- Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, 3420 North Broad Street, Philadelphia, PA, 19140, USA.,Department of Microbiology and Immunology Temple University School of Medicine, Temple University Hospital, Philadelphia, Pennsylvania, USA
| | - Elisabetta Liverani
- Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, 3420 North Broad Street, Philadelphia, PA, 19140, USA
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Polasky C, Wendt F, Pries R, Wollenberg B. Platelet Induced Functional Alteration of CD4 + and CD8 + T Cells in HNSCC. Int J Mol Sci 2020; 21:ijms21207507. [PMID: 33053760 PMCID: PMC7588893 DOI: 10.3390/ijms21207507] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/09/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
Platelets (PLT) are the second most abundant cell type in human blood and exert various immune-regulatory functions under both physiological and pathological conditions. In fact, immune cell regulation via platelets has been demonstrated in several studies within the past decade. However, the exact mechanisms behind T cell regulation remain poorly understood. We questioned whether the formation of aggregates of platelets and T cells has an impact on T-cell functions. In the present study, we stimulated PBMC cultures with anti-CD3 and anti-CD28 mABs and cultured them at a PLT: PBMC ratio of 1:1 or 100:1. After 24, 48, and 72 h, PD-1, PD-L1 expression, and proliferation were analyzed on T cells using flow cytometry. Cytokine production was measured in PHA stimulated CD4 cells after 6 h. We found a significant platelet-mediated decrease in PD-1 and PD-L1 expression, proliferation, as well as IFN-γ and TNF-α production. Perturbations also at least partially remained after spatial separation of PLTs from PBMCs in Transwell-assays. T cell-platelet aggregates showed similar levels of activation markers, proliferation, and secreted cytokines as their non-complexed counterparts. Results indicate a platelet mediated regulation of T cells via direct and indirect contact, but only mediocre effects of the complex formation itself.
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Affiliation(s)
- Christina Polasky
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
- Correspondence: ; Tel.: +49-451-500-42129
| | - Franziska Wendt
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
| | - Ralph Pries
- Department of Otorhinolaryngology, University Hospital of Schleswig-Holstein, 23538 Lübeck, Germany; (F.W.); (R.P.)
| | - Barbara Wollenberg
- Department of Otorhinolaryngology, University Hospital MRI, Technical University, 81675 München, Germany;
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Tan S, Li S, Min Y, Gisterå A, Moruzzi N, Zhang J, Sun Y, Andersson J, Malmström RE, Wang M, Berggren PO, Schlisio S, Liao W, Ketelhuth DFJ, Ma C, Li N. Platelet factor 4 enhances CD4 + T effector memory cell responses via Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis. J Thromb Haemost 2020; 18:2685-2700. [PMID: 32671959 DOI: 10.1111/jth.15005] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/10/2020] [Accepted: 07/08/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Cell metabolism drives T cell functions, while platelets regulate overall CD4+ T cell immune responses. OBJECTIVE To investigate if platelets influence cell metabolism and thus regulate CD4+ T effector memory cell (Tem) responses. METHODS Human CD4+ Tem cells were activated with αCD3/αCD28 and cultured without or with platelets or platelet-derived mediators. RESULTS Polyclonal stimulation induced rapid and marked Th1 and Treg cell activation of CD4+ Tem cells. Platelet co-culture enhanced Th1 response transiently, while it persistently enhanced Treg cell activation of Tem cells, with an enhancement that plateaued by day 3. Platelet factor 4 (PF4) was the key platelet-derived mediator regulating CD4+ Tem cell responses, which involved cellular metabolisms as indicated by mass spectrometric analyses. PF4 exerted its effects via its receptor CXCR3, attenuated Akt activity, and reduced PGC1α phosphorylation, and resulted in elevations of PGC1α function and mitochondrial transcription factor A (TFAM) synthesis. The latter increased mitochondrial biogenesis, and subsequently enhanced Th1 and Treg responses. Consistent with these observations, inhibition of mitochondrial function by rotenone counteracted the enhancements by recombinant PF4, and TFAM overexpression by TFAM-adenovirus infection mimicked PF4 effects. Furthermore, increased mitochondrial mass elevated oxygen consumption, and enhanced adenosine triphosphate and reactive oxygen species production, which, in turn, stimulated Th1 (T-bet) and Treg (FoxP3) transcription factor expression and corresponding CD4+ T effector cell responses. CONCLUSIONS Platelets enhance CD4+ T cell responses of Tem cells through PF4-dependent and Akt-PGC1α-TFAM signaling-mediated mitochondrial biogenesis. Hence, PF4 may be a promising intervention target of platelet-regulated immune responses.
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Affiliation(s)
- Shuai Tan
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institutet, Stockholm, Sweden
| | - Shuijie Li
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Yanan Min
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institutet, Stockholm, Sweden
| | - Anton Gisterå
- Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Noah Moruzzi
- Department of Molecular Medicine and Surgery, Rolf Ruft Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Junhao Zhang
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institutet, Stockholm, Sweden
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Sun
- Shandong University Cheeloo Medical College, Institute of Immunology, Jinan, China
| | - John Andersson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Rickard E Malmström
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institutet, Stockholm, Sweden
- Department of Laboratory Medicine, Clinical Pharmacology, Karolinska University Hospital-Solna, Stockholm, Sweden
| | - Miao Wang
- Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Per-Olof Berggren
- Department of Molecular Medicine and Surgery, Rolf Ruft Research Center, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Schlisio
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Daniel F J Ketelhuth
- Department of Medicine-Solna, Cardiovascular Medicine Unit, Karolinska Institutet, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Chunhong Ma
- Shandong University Cheeloo Medical College, Institute of Immunology, Jinan, China
| | - Nailin Li
- Department of Medicine-Solna, Clinical Epidemiology Unit, Clinical Pharmacology Group, Karolinska Institutet, Stockholm, Sweden
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Cai S, Chen Y, Lin S, Ye C, Zheng F, Dong L. Multiple Processes May Involve in the IgG4-RD Pathogenesis: An Integrative Study via Proteomic and Transcriptomic Analysis. Front Immunol 2020; 11:1795. [PMID: 32973752 PMCID: PMC7468437 DOI: 10.3389/fimmu.2020.01795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/06/2020] [Indexed: 01/13/2023] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is a newly defined disease entity, while the exact pathogenesis is still not clear. Identifying the characters of IgG4-RD in proteomic and transcriptomic aspects will be critical to investigate the potential pathogenic mechanisms of IgG4-RD. We performed proteomic analysis realized with iTRAQ technique for serum samples from eight treatment-naive IgG4-RD patients and eight healthy volunteers, and tissue samples from two IgG4-RD patients and two non-IgG4-RD patients. Transcriptomic data (GSE40568 and GSE66465) was obtained from the GEO Dataset for validation. The weighted correlation network analysis (WGCNA) was applied to detect the gene modules correlated with IgG4-RD. KEGG pathway analysis was used to investigate pathways enriched in IgG4-RD samples. As a result, a total of 980 differentially expressed proteins (DEPs) in tissue and 94 DEPs in serum were identified between IgG4-RD and control groups. Three hundred fifty-four and two hundred forty-seven genes that most correlated with IgG4-RD were detected by WGCNA analysis in tissue and PBMC, respectively. We also found that DEPs in IgG4-RD samples were enriched in several immune-related activities including bacterial/viral infections and platelet activation as well as some immune related signaling pathways. In conclusion, we identified multiple processes/factors and several signaling pathways that may involve in the IgG4-RD pathogenesis, and found out some potential therapeutic targets for IgG4-RD.
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Affiliation(s)
- Shaozhe Cai
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Chen
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - ShengYan Lin
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Ye
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fang Zheng
- Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- NHC Key Laboratory of Organ Transplantation, Ministry of Education, Chinese Academy of Medical Sciences, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Sanz-Martínez MT, Moga E, Sánchez Martínez MA, Zamora Atenza C, Vidal S, Juárez C, Puig L. High Levels of Platelet-Lymphocyte Complexes in Patients with Psoriasis Are Associated with a Better Response to Anti-TNF-α Therapy. J Invest Dermatol 2020; 140:1176-1183. [PMID: 31778714 DOI: 10.1016/j.jid.2019.08.457] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 08/15/2019] [Accepted: 08/16/2019] [Indexed: 02/06/2023]
Abstract
Psoriasis is currently considered to be an immune-mediated disease whose patho-mechanisms involve platelet activation, which seems to correlate with the activity of the disease. Platelet activation is associated with the formation of platelet-lymphocyte complexes (PLyC), although their significance remains unknown. Moreover, biological treatments that target tumor necrosis factor-α (TNF-α) reduce platelet activation. To clarify the significance of PLyC, we compared their levels in patients with psoriasis with those of healthy donors and determined whether platelet binding modifies the secretion of IL-17A by T helper cells. Finally, we assessed the effect of anti-TNF-α treatment on PLyC in responder and non-responder patients with psoriasis. Ours results demonstrated an increase in PLyC in patients with psoriasis. Moreover, the percentage of IL-17-secreting cells was observed to be higher in the platelet-lymphocyte complex population, and these cells tended to secrete greater amounts of IL-17A. Psoriasis patients treated with anti-TNF-α normalized platelet-lymphocyte complex values, and the basal percentage of platelet-T helper lymphocyte complexes was significantly higher in the responder group. In conclusion, PLyC are increased in psoriasis patients, and the number of complexes decreases in response to anti-TNF-α treatment, specifically in the responder group of patients. This finding suggests that PLyC are a prognostic biomarker of response to anti-TNF-α therapy, but prospective studies are necessary to verify these results in patients with psoriasis.
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Affiliation(s)
| | - Esther Moga
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Carlos Zamora Atenza
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Silvia Vidal
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Cándido Juárez
- Department of Immunology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Lluís Puig
- Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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Abstract
Rheumatoid arthritis (RA) is an autoimmune disease in which a variety of circulating pro-inflammatory cells and dysregulated molecules are involved in disease aetiology and progression. Platelets are an important cellular element in the circulation that can bind several dysregulated molecules (such as collagen, thrombin and fibrinogen) that are present both in the synovium and the circulation of patients with RA. Platelets not only respond to dysregulated molecules in their environment but also transport and express their own inflammatory mediators, and serve as regulators at the boundary between haemostasis and immunity. Activated platelets also produce microparticles, which further convey signalling molecules and receptors to the synovium and circulation, thereby positioning these platelet-derived particles as strategic regulators of inflammation. These diverse functions come together to make platelets facilitators of cellular crosstalk in RA. Thus, the receptor functions, ligand binding potential and dysregulated signalling pathways in platelets are becoming increasingly important for treatment in RA. This Review aims to highlight the role of platelets in RA and the need to closely examine platelets as health indicators when designing effective pharmaceutical targets in this disease.
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Margraf A, Zarbock A. Platelets in Inflammation and Resolution. THE JOURNAL OF IMMUNOLOGY 2019; 203:2357-2367. [DOI: 10.4049/jimmunol.1900899] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 08/30/2019] [Indexed: 12/22/2022]
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Platelets in Host Defense: Experimental and Clinical Insights. Trends Immunol 2019; 40:922-938. [PMID: 31601520 DOI: 10.1016/j.it.2019.08.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/13/2019] [Accepted: 08/13/2019] [Indexed: 12/13/2022]
Abstract
Platelets are central players in thrombosis and hemostasis but are increasingly recognized as key components of the immune system. They shape ensuing immune responses by recruiting leukocytes, and support the development of adaptive immunity. Recent data shed new light on the complex role of platelets in immunity. Here, we summarize experimental and clinical data on the role of platelets in host defense against bacteria. Platelets bind, contain, and kill bacteria directly; however, platelet proinflammatory effector functions and cross-talk with the coagulation system, can also result in damage to the host (e.g., acute lung injury and sepsis). Novel clinical insights support this dichotomy: platelet inhibition/thrombocytopenia can be either harmful or protective, depending on pathophysiological context. Clinical studies are currently addressing this aspect in greater depth.
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Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP. Mol Cell Biol 2019; 39:MCB.00365-18. [PMID: 30833485 DOI: 10.1128/mcb.00365-18] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 02/26/2019] [Indexed: 12/27/2022] Open
Abstract
The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knockout mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knockout mice (ADAPfl/fl PF4-Cretg) (PF4, platelet factor 4). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even under stimulation conditions. ADAPfl/fl PF4-Cretg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and transforming growth factor β1 (TGF-β1). In vitro, platelets from these mice revealed reduced P-selectin expression, lower levels of TGF-β1 release, diminished integrin αIIbβ3 activation, and decreased fibrinogen binding after stimulation with podoplanin, the ligand of C-type lectin-like receptor 2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of phospholipase Cγ2 (PLCγ2) and extracellular signal-regulated kinase 1/2 (ERK1/2). Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-β1 early after T cell transfer reduced EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.
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Cafaro G, Bartoloni E, Alunno A, Gerli R. Platelets: a potential target for rheumatoid arthritis treatment? Expert Rev Clin Immunol 2018; 15:1-3. [PMID: 30392437 DOI: 10.1080/1744666x.2019.1544071] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Giacomo Cafaro
- a Section of Rheumatology, Department of Medicine , University of Perugia , Perugia , Italy
| | - Elena Bartoloni
- a Section of Rheumatology, Department of Medicine , University of Perugia , Perugia , Italy
| | - Alessia Alunno
- a Section of Rheumatology, Department of Medicine , University of Perugia , Perugia , Italy
| | - Roberto Gerli
- a Section of Rheumatology, Department of Medicine , University of Perugia , Perugia , Italy
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40
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Nazy I, Clare R, Staibano P, Warkentin TE, Larché M, Moore JC, Smith JW, Whitlock RP, Kelton JG, Arnold DM. Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia. J Thromb Haemost 2018; 16:1402-1412. [PMID: 29723924 DOI: 10.1111/jth.14132] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Indexed: 01/31/2023]
Abstract
Essentials The immunogenesis of Heparin-induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)-heparin occurs early in life, before any heparin exposure. PF4 and PF4-heparin complexes induce the proliferation of CD14+ cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT. SUMMARY Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [3 H]thymidine uptake and 5-ethynyl-2'-deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14+ cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin-10 and transforming growth factor-β1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT.
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Affiliation(s)
- I Nazy
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - R Clare
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - P Staibano
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - T E Warkentin
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - M Larché
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - J C Moore
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - J W Smith
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - R P Whitlock
- Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
- Division of Cardiac Surgery, McMaster University, Hamilton, Ontario, Canada
| | - J G Kelton
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
| | - D M Arnold
- Department of Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Centre for Transfusion Research, McMaster University, Hamilton, Ontario, Canada
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Affandi AJ, Silva‐Cardoso SC, Garcia S, Leijten EFA, van Kempen TS, Marut W, van Roon JAG, Radstake TRDJ. CXCL4 is a novel inducer of human Th17 cells and correlates with IL-17 and IL-22 in psoriatic arthritis. Eur J Immunol 2018; 48:522-531. [PMID: 29193036 PMCID: PMC5888178 DOI: 10.1002/eji.201747195] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 10/18/2017] [Accepted: 11/23/2017] [Indexed: 11/06/2022]
Abstract
CXCL4 regulates multiple facets of the immune response and is highly upregulated in various Th17-associated rheumatic diseases. However, whether CXCL4 plays a direct role in the induction of IL-17 production by human CD4+ T cells is currently unclear. Here, we demonstrated that CXCL4 induced human CD4+ T cells to secrete IL-17 that co-expressed IFN-γ and IL-22, and differentiated naïve CD4+ T cells to become Th17-cytokine producing cells. In a co-culture system of human CD4+ T cells with monocytes or myeloid dendritic cells, CXCL4 induced IL-17 production upon triggering by superantigen. Moreover, when monocyte-derived dendritic cells were differentiated in the presence of CXCL4, they orchestrated increased levels of IL-17, IFN-γ, and proliferation by CD4+ T cells. Furthermore, the CXCL4 levels in synovial fluid from psoriatic arthritis patients strongly correlated with IL-17 and IL-22 levels. A similar response to CXCL4 of enhanced IL-17 production by CD4+ T cells was also observed in patients with psoriatic arthritis. Altogether, we demonstrate that CXCL4 boosts pro-inflammatory cytokine production especially IL-17 by human CD4+ T cells, either by acting directly or indirectly via myeloid antigen presenting cells, implicating a role for CXCL4 in PsA pathology.
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Affiliation(s)
- Alsya J. Affandi
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Sandra C. Silva‐Cardoso
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Samuel Garcia
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Emmerik F. A. Leijten
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Tessa S. van Kempen
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Wioleta Marut
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Joel A. G. van Roon
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
| | - Timothy R. D. J. Radstake
- Laboratory of Translational ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtThe Netherlands
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From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol Int 2018; 38:959-974. [PMID: 29492586 PMCID: PMC5954012 DOI: 10.1007/s00296-018-4001-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 02/22/2018] [Indexed: 12/14/2022]
Abstract
Thrombosis and cardiovascular complications are common manifestations of a variety of pathological conditions, including infections and chronic inflammatory diseases. Hence, there is great interest in determining the hitherto unforeseen immune role of the main blood coagulation executor-the platelet. Platelets store and release a plethora of immunoactive molecules, generate microparticles, and interact with cells classically belonging to the immune system. The observed effects of platelet involvement in immune processes, especially in autoimmune diseases, are conflicting-from inciting inflammation to mediating its resolution. An in-depth understanding of the role of platelets in inflammation and immunity could open new therapeutic pathways for patients with autoimmune disorders. This review aims to summarize the current knowledge on the role of platelets in the patomechanisms of autoimmune disorders and suggests directions for future research.
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Campos-González R, Skelley AM, Gandhi K, Inglis DW, Sturm JC, Civin CI, Ward T. Deterministic Lateral Displacement: The Next-Generation CAR T-Cell Processing? SLAS Technol 2018; 23:338-351. [DOI: 10.1177/2472630317751214] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
| | | | | | - David W. Inglis
- Department of Engineering, Macquarie University, Sydney, NSW, Australia
| | - James C. Sturm
- Princeton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ, USA
| | - Curt I. Civin
- Center for Stem Cell Biology & Regenerative Medicine and Greenebaum Cancer Center, Departments of Pediatrics and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Tony Ward
- GPB Scientific LLC, Richmond, VA, USA
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von Hundelshausen P, Duchene J. Platelet-derived chemokines in atherosclerosis. Hamostaseologie 2017; 35:137-41. [DOI: 10.5482/hamo-14-11-0058] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/22/2014] [Indexed: 02/01/2023] Open
Abstract
SummaryIn atherosclerosis, activated platelets have been recently recognised not only to participate in thrombotic events but also to play an essential role in the development of atherosclerotic lesions. Upon their activation, platelets release several pro-inflammatory mediators including chemokines. Chemokines are key molecules in inflammation as they are able to recruit leukocytes, modulate their activation/differentiation and control their proliferation/apoptosis.In this review we will discuss recent findings regarding the specific roles of chemokines released by platelets on leukocytes and their effects on atherosclerosis.
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Platelet releasate promotes breast cancer growth and angiogenesis via VEGF-integrin cooperative signalling. Br J Cancer 2017; 117:695-703. [PMID: 28697175 PMCID: PMC5572171 DOI: 10.1038/bjc.2017.214] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 06/13/2017] [Accepted: 06/14/2017] [Indexed: 12/21/2022] Open
Abstract
Background: Selective platelet release of pro- or anti-angiogenic factors distinctly regulated angiogenesis. We hypothesised that selective release of platelet angiogenic factors could differently regulate tumour growth. Methods: Breast cancer cell proliferation, cancer cell-induced endothelial tube formation in vitro, and tumour growth in vivo were studied in the presence of protease-activated receptor 1-stimulated platelet releasate (PAR1-PR; rich in pro-angiogenic factors) or PAR4-PR (rich in anti-angiogenic factors). Results: The PAR1-PR and PAR4-PR supplementation (10%) similarly enhanced cell proliferation of MCF-7 and MDA-MB-231 breast cancer cells. The cancer cells triggered capillary-like tube formation of endothelial cells that was further enhanced by pro-angiogenic factor-rich PAR1-PR. The VEGF, but not SDF-1α, receptor blockade abolished PAR1-PR/PAR4-PR-enhanced cancer cell proliferation. Integrin blockade by RGDS had identical effects as VEGF inhibition. The Src and ERK inhibition diminished, whereas PI3K and PKC blockade abolished platelet releasate-enhanced cancer cell proliferation. Using a model of subcutaneous implantation of MDA-MB-231 cells in nude mice, PAR1-PR enhanced tumour growth more markedly than PAR4-PR, and seemed to achieve the exaggeration by promoting more profound tumour angiogenesis. Conclusions: Platelet releasate increases breast cancer cell proliferation through VEGF–integrin cooperative signalling. Pro-angiogenic factor-rich platelet releasate enhances cancer cell-induced angiogenesis more markedly, and thus exaggerates tumour growth in vivo.
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Zamora C, Cantó E, Nieto JC, Bardina J, Diaz-Torné C, Moya P, Magallares B, Ortiz MA, Julià G, Juarez C, Llobet JM, Vidal S. Binding of Platelets to Lymphocytes: A Potential Anti-Inflammatory Therapy in Rheumatoid Arthritis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2017; 198:3099-3108. [PMID: 28250158 DOI: 10.4049/jimmunol.1601708] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 02/03/2017] [Indexed: 12/15/2022]
Abstract
Soluble factors released from platelets can modulate the immune response of leukocytes. We and others have recently found that T lymphocytes with bound platelets have reduced proliferation and IFN-γ and IL-17 production. Thus, we speculate that if we induce the binding of platelets to lymphocytes, we will be able to regulate the inflammatory response. When we cocultured platelets with lymphocytes at different ratios, we were able to increase the percentage of lymphocytes with bound platelets. The coculture of platelets with lymphocytes in the presence of stimulation decreased the production of IFN-γ and TNF-α, T cell proliferation, and the expression of CD25, PD-L1, and SLAM. However, this coculture increased CD39 expression. All of these effects were dependent on the dose of platelets and operated indistinctly with platelets from different healthy donors. When platelets were cocultured in the same compartment with lymphocytes, we observed less IFN-γ and TNF-α production and T lymphocyte proliferation than in cultures with platelets separated from lymphocytes by a 0.4-μm pore size filter. The binding of platelets to lymphocytes was blocked with anti-P-selectin Abs, and when this occurred we observed higher IFN-γ and TNF-α production than in nonblocked conditions. The cocultures of platelets with synovial fluid cells from rheumatoid arthritis patients reduced inflammatory cytokine production and increased IL-10 production. These results suggest that platelet binding to lymphocytes effectively regulates T lymphocyte function. This mechanism could be easily applied to reduce inflammatory responses.
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Affiliation(s)
- Carlos Zamora
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain;
| | - Elisabet Cantó
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
| | - Juan C Nieto
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
| | - Jorge Bardina
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
| | - Cesar Diaz-Torné
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
- Unitat Reumatologia, Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain; and
| | - Patricia Moya
- Unitat Reumatologia, Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain; and
| | - Berta Magallares
- Unitat Reumatologia, Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain; and
| | - M Angels Ortiz
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
| | - Germà Julià
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
| | - Candido Juarez
- Departament Immunologia, Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain
| | - Josep M Llobet
- Unitat Reumatologia, Hospital de la Santa Creu i Sant Pau, 08026 Barcelona, Spain; and
| | - Silvia Vidal
- Departament Immunologia, Institut Recerca Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain;
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Platelets modulate the immune response following trauma by interaction with CD4+ T regulatory cells in a mouse model. Immunol Res 2016; 64:508-17. [PMID: 26471021 DOI: 10.1007/s12026-015-8726-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
CD4+ T regulatory cells (Tregs) play a pivotal role in the anti-inflammatory immune response following trauma. The mechanisms of CD4+ Treg activation are mostly unknown. Here, we hypothesize that platelets regulate CD4+ Treg activation following trauma. In a murine burn injury model (male C57Bl/6N mice), depletion of platelets or CD4+ Tregs was conducted. Draining lymph nodes, blood and spleen were harvested 2 h and 7 days after trauma. CD4+ Treg activation was measured using phospho- and conventional flow cytometry. Platelet activation was analyzed using thromboelastometry and flow cytometry. Trauma differentially activates CD4+ T cells, early after trauma only CD4+ Tregs are activated. Following burn injury, platelets augment the activation of CD4+ Tregs. This effect could only be seen early after trauma. While CD4+ Tregs influence hemostasis early following trauma, platelet activation markers were unchanged. Beyond their role in hemostasis, platelets are able to modulate the immunologic host response to trauma-induced injury by augmenting the activation of CD4+ Tregs. CD4+ Treg activation following trauma is considered protective. In addition, CD4+ Tregs are capable of modulating the hemostatic function of platelets. For the first time, we could show reciprocal activation of platelets and CD4+ Tregs as part of the protective immune response following trauma.
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TGF-β1 along with other platelet contents augments Treg cells to suppress anti-FVIII immune responses in hemophilia A mice. Blood Adv 2016; 1:139-151. [PMID: 28164173 DOI: 10.1182/bloodadvances.2016001453] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Platelets are a rich source of many cytokines and chemokines including transforming growth factor β 1 (TGF-β1). TGF-β1 is required to convert conventional CD4+ T (Tconv) cells into induced regulatory T (iTreg) cells that express the transcription factor Foxp3. Whether platelet contents will affect Treg cell properties has not been explored. In this study, we show that unfractionated platelet lysates (pltLys) containing TGF-β1 efficiently induced Foxp3 expression in Tconv cells. The common Treg cell surface phenotype and in vitro suppressive activity of unfractionated pltLys-iTreg cells were similar to those of iTreg cells generated using purified TGF-β1 (purTGFβ-iTreg) cells. However, there were substantial differences in gene expression between pltLys-iTreg and purTGFβ-iTreg cells, especially in granzyme B, interferon γ, and interleukin-2 (a 30.99-, 29.18-, and 17.94-fold difference, respectively) as determined by gene microarray analysis. In line with these gene signatures, we found that pltLys-iTreg cells improved cell recovery after transfer and immune suppressive function compared with purTGFβ-iTreg cells in factor VIII (FVIII)-deficient (F8null, hemophilia A model) mice after recombinant human FVIII (rhF8) infusion. Acute antibody-mediated platelet destruction in F8null mice followed by rhF8 infusion increased the number of Treg cells and suppressed the antibody response to rhF8. Consistent with these data, ex vivo proliferation of F8-specific Treg cells from platelet-depleted animals increased when restimulated with rhF8. Together, our data suggest that pltLys-iTreg cells may have advantages in emerging clinical applications and that platelet contents impact the properties of iTreg cells induced by TGF-β1.
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Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin. Blood 2016; 127:1976-86. [PMID: 26903549 DOI: 10.1182/blood-2015-04-640300] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 02/09/2016] [Indexed: 12/22/2022] Open
Abstract
Self-tolerance and immune homeostasis are orchestrated by FOXP3(+)regulatory T cells (Tregs). Recent data have revealed that upon stimulation, Tregs may exhibit plasticity toward a proinflammatory phenotype, producing interleukin 17 (IL-17) and/or interferon γ (IFN-γ). Such deregulation of Tregs may contribute to the perpetuation of inflammatory processes, including graft-versus-host disease. Thus, it is important to identify immunomodulatory factors influencing Treg stability. Platelet-derived microparticles (PMPs) are involved in hemostasis and vascular health and have recently been shown to be intimately involved in (pathogenic) immune responses. Therefore, we investigated whether PMPs have the ability to affect Treg plasticity. PMPs were cocultured with healthy donor peripheral blood-derived Tregs that were stimulated with anti-CD3/CD28 monoclonal antibodies in the presence of IL-2, IL-15, and IL-1β. PMPs prevented the differentiation of peripheral blood-derived Tregs into IL-17- and IFN-γ-producing cells, even in the presence of the IL-17-driving proinflammatory cytokine IL-1β. The mechanism of action by which PMPs prevent Treg plasticity consisted of rapid and selective P-selectin-dependent binding of PMPs to a CCR6(+)HLA-DR(+)memory-like Treg subset and their ability to inhibit Treg proliferation, in part through CXCR3 engagement. The findings that ~8% of Tregs in the circulation of healthy individuals are CD41(+)P-selectin(+)and that distinct binding of patient plasma PMPs to Tregs was observed support in vivo relevance. These findings open the exciting possibility that PMPs actively regulate the immune response at sites of (vascular) inflammation, where they are known to accumulate and interact with leukocytes, consolidating the (vascular) healing process.
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Starossom SC, Veremeyko T, Yung AWY, Dukhinova M, Au C, Lau AY, Weiner HL, Ponomarev ED. Platelets Play Differential Role During the Initiation and Progression of Autoimmune Neuroinflammation. Circ Res 2015; 117:779-92. [PMID: 26294656 DOI: 10.1161/circresaha.115.306847] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/20/2015] [Indexed: 11/16/2022]
Abstract
RATIONALE Platelets are known to participate in vascular pathologies; however, their role in neuroinflammatory diseases, such as multiple sclerosis (MS), is unknown. Autoimmune CD4 T cells have been the main focus of studies of MS, although the factors that regulate T-cell differentiation toward pathogenic T helper-1/T helper-17 phenotypes are not completely understood. OBJECTIVE We investigated the role of platelets in the modulation of CD4 T-cell functions in patients with MS and in mice with experimental autoimmune encephalitis, an animal model for MS. METHODS AND RESULTS We found that early in MS and experimental autoimmune encephalitis, platelets degranulated and produced soluble factors serotonin (5-hydroxytryptamine), platelet factor 4, and platelet-activating factor, which specifically stimulated differentiation of T cells toward pathogenic T helper-1, T helper-17, and interferon-γ/interleukin-17-producing CD4 T cells. At the later stages of MS and experimental autoimmune encephalitis, platelets became exhausted in their ability to produce proinflammatory factors and stimulate CD4 T cells but substantially increased their ability to form aggregates with CD4 T cells. Formation of platelet-CD4 T-cell aggregates involved the interaction of CD62P on activated platelets with adhesion molecule CD166 on activated CD4 T cells, contributing to downmodulation of CD4 T-cell activation, proliferation, and production of interferon-γ. Blocking of formation of platelet-CD4 T-cell aggregates during progression of experimental autoimmune encephalitis substantially enhanced proliferation of CD4 T cells in the central nervous system and the periphery leading to exacerbation of the disease. CONCLUSION Our study indicates differential roles for platelets in the regulation of functions of pathogenic CD4 T cells during initiation and progression of central nervous system autoimmune inflammation.
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Affiliation(s)
- Sarah C Starossom
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Tatyana Veremeyko
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Amanda W Y Yung
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Marina Dukhinova
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Cheryl Au
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Alexander Y Lau
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Howard L Weiner
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong
| | - Eugene D Ponomarev
- From the Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA (S.C.S., H.L.W., E.D.P.); Institute for Medical Immunology and NeuroCure, Department of Experimental Neuroimmunology, Charité - Universitätsmedizin Berlin, Berlin, Germany (S.C.S.); and School of Biomedical Sciences, Faculty of Medicine (T.V., A.W.Y.Y., M.D., E.D.P.) and Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital (C.A., A.Y.L.), The Chinese University of Hong Kong, Hong Kong.
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