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Platelet‐Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus
Author(s) -
Lood Christian,
Tydén Helena,
Gullstrand Birgitta,
Jönsen Andreas,
Källberg Eva,
Mörgelin Matthias,
Kahn Robin,
Gunnarsson Iva,
Leanderson Tomas,
Ivars Fredrik,
Svenungsson Elisabet,
Bengtsson Anders A.
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39656
Subject(s) - platelet , s100a8 , immunology , medicine , platelet activation , cell , inflammation , chemistry , biochemistry
Objective Levels of S100A8/A9, a proinflammatory and prothrombotic protein complex, are increased in several diseases, and high levels predispose to cardiovascular disease (CVD). Recently, platelet S100A8/A9 synthesis was described in mice and humans in relation to CVD. The aim of this study was to investigate the role of platelet S100A8/A9 in systemic lupus erythematosus (SLE), a disease with markedly increased cardiovascular morbidity, as well as the exact platelet distribution of the S100A8/A9 proteins. Methods The occurrence and distribution of platelet S100A8/A9 protein were detected by enzyme‐linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry in healthy controls (n = 79) and in 2 individual cohorts of SLE patients (n = 148 and n = 318, respectively) and related to cardiovascular morbidity. Results We observed that human platelets expressed S100A8/A9 proteins, and that these were localized in close proximity to intracellular membranes and granules as well as on the cell surface upon activation with physiologic and pathophysiologic stimuli. Interestingly, S100A8/A9 was enriched at sites of membrane interactions, indicating a role of S100A8/A9 in cell–cell communication. S100A8/A9 levels were highly regulated by interferon‐α, both in vivo and in vitro. Patients with SLE had increased platelet S100A8/A9 content compared with healthy individuals. Increased levels of platelet S100A8/A9 were associated with CVD, particularly myocardial infarction (odds ratio 4.8, 95% confidence interval 1.5–14.9, P = 0.032 [adjusted for age, sex, and smoking]). Conclusion Platelets contain S100A8/A9 in membrane‐enclosed vesicles, enabling rapid cell surface deposition upon activation. Furthermore, platelet S100A8/A9 protein levels were increased in SLE patients, particularly in those with CVD, and may be a future therapeutic target.