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Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3-Induced
Irene Müller1, Thomas Vogl1, Kathleen Pappritz1
1From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.).
Insights
Alarmins S100A8 and S100A9 worsen Coxsackievirus B3-induced myocarditis. Targeting these proteins may offer new treatments for inflammatory cardiomyopathies.
Area of Science:
- Cardiovascular Research
- Immunology
- Virology
Background:
- S100A8 and S100A9 are damage-associated molecular patterns involved in inflammation and viral infections.
- Their role in Coxsackievirus B3 (CVB3)-induced myocarditis requires further investigation.
Purpose of the Study:
- To investigate the role of S100A8 and S100A9 in CVB3-induced myocarditis.
Main Methods:
- Analysis of S100A8 and S100A9 expression in patient biopsies and CVB3-infected mouse models.
- Assessment of cardiac function, inflammation, oxidative stress, and viral load in wild-type and knockout mice.
- In vitro studies using cell cultures (HL-1 cells and RAW macrophages) to evaluate the effects of S100A8 and S100A9 on viral replication and inflammatory responses.
Main Results:
- Elevated S100A8 and S100A9 mRNA in CVB3-positive myocarditis patients.
- CVB3 infection impaired left ventricular function in mice, correlating with increased S100A8/S100A9 protein.
- S100A9 knockout mice showed improved cardiac function, reduced inflammation, and lower viral load.
- Exogenous S100A8 induced severe myocarditis in knockout mice.
- In vitro, S100A8/S100A9 increased oxidative stress and viral load in HL-1 cells and MIP-2 expression in macrophages.
Conclusions:
- S100A8 and S100A9 exacerbate CVB3-induced myocarditis.
- These alarmins represent potential therapeutic targets for inflammatory cardiomyopathies.
Background:
The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis.
Methods And Results:
S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells.
Conclusions:
S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
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