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Platelet-Derived S100A8/A9 and Cardiovascular Disease in Systemic Lupus Erythematosus
Christian Lood1, Helena Tydén1, Birgitta Gullstrand1
1Lund University and Skåne University Hospital, Lund, Sweden.
Insights
Platelets store and release S100A8/A9 proteins, which are elevated in systemic lupus erythematosus (SLE) patients. Increased platelet S100A8/A9 is linked to cardiovascular disease (CVD) in SLE.
Area of Science:
- Immunology
- Cardiovascular Biology
- Hematology
Background:
- S100A8/A9 is a proinflammatory and prothrombotic protein complex implicated in cardiovascular disease (CVD).
- Platelet synthesis of S100A8/A9 has been recently described in relation to CVD.
- Systemic lupus erythematosus (SLE) is associated with significantly increased cardiovascular morbidity.
Purpose of the Study:
- To investigate the role of platelet S100A8/A9 in SLE.
- To determine the distribution of S100A8/A9 proteins within human platelets.
- To assess the association between platelet S100A8/A9 levels and cardiovascular morbidity in SLE patients.
Main Methods:
- Enzyme-linked immunosorbent assay, electron microscopy, Western blotting, and flow cytometry were used.
- Platelet S100A8/A9 occurrence and distribution were analyzed.
- Data were collected from healthy controls (n=79) and two SLE patient cohorts (n=148 and n=318).
Main Results:
- Human platelets express S100A8/A9, localized intracellularly and on the cell surface upon activation.
- S100A8/A9 accumulates at sites of membrane interactions, suggesting a role in cell communication.
- SLE patients exhibited higher platelet S100A8/A9 levels compared to healthy individuals.
- Elevated platelet S100A8/A9 was associated with CVD, particularly myocardial infarction (OR 4.8, P=0.032).
Conclusions:
- Platelets store S100A8/A9 in vesicles for rapid release upon activation.
- Increased platelet S100A8/A9 levels in SLE patients, especially those with CVD, highlight its potential clinical significance.
- Platelet S100A8/A9 may represent a future therapeutic target for managing CVD in SLE.
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.
