Extracellular vesicles cargo of the proteolytically active ADAM proteases shape the inflammatory response and drive disease severity

Background

Extracellular vesicles (EVs) like exosomes play an essential role in orchestrating the immune response and influencing the performance of immune cells. Members of the ‘a disintegrin and metalloproteinase’ (ADAM) family, particularly ADAM8, ADAM10, and ADAM17, have the capability to proteolytically cleave transmembrane molecules close to the plasma membrane, a process called ectodomain shedding. Therefore, we aimed to investigate the release of the mentioned ADAMs in EVs and their influence on disease severity.

 

Methods

Exosomes were isolated from the plasma of patients with bacterial and viral pneumonia (of varying severities) as well as from primary human neutrophils by ultracentrifugation followed by sucrose fractionation to evaluate the activity of ADAM proteases in EVs and their influence on recipient cells. In addition, EVs were isolated from the sulcus fluid of periodontal disease patients and evaluated for their tissue destruction effect.

 

Results

Our research has demonstrated that ADAMs released in exosomes are proteolytically active and capable of performing proteolysis in trans. These exosomes, released by leukocytes, are transferred to the circulation, causing effects on distinct organs. The exosomal activity of ADAM10 and ADAM17 induced changes in calcium signaling in cardiomyocytes and disrupted the integrity of the endothelial barrier. Furthermore, the exosomal cargos and interacting molecules account for the tissue-destructive capacity, which we have observed in samples from periodontal disease patients and upon in vitro Porphyromonas gingivalis infection of oral keratinocytes, respectively.  

 

Conclusion

Our results highlight the significance of ADAM8, ADAM10, and ADAM17 as exosomal cargo during infection, emphasizing the need to develop new prognostic and therapeutic tools that should be addressed in further preclinical and translational studies.

 

Keywords

Exosomes, metalloproteinase, infection, proteolysis, pneumonia.

 

Authors

Ahmad Aljohmani1, Robert Bals2, Martin Witzenrath3, Daniela Yildiz1 (Corresponding Author: Ahmad.aljohmani[at]uks[dot]eu)

 

1 Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, Homburg, Germany.

2 Department for Internal Medicine V – Pulmonology, Allergology, Intensive Care Medicine. Saarland University, Homburg, Germany

3 Department of Infectious Diseases, Respiratory Medicine and Critical Care, Charité – Universitätsmedizin Berlin.

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