Leukocytic ADAM10 and ADAM17 modulate disease severity and systemic outcome in bacterial and viral pneumonia.

Abstract

BACKGROUND: Pneumonia caused by viral or bacterial pathogens such as severe acute respiratory syndrome coronavirus 2 ormay result in life-threatening disease with a strong contribution of protease dysregulation. The present study aimed to systematically characterise the contribution of ADAM10 and ADAM17 on leukocytes and circulating exosomes to viral and bacterial pneumonia. METHODS: The analysis of coronavirus disease 2019 (COVID-19) and bacterial pneumonia patient samples was combined withexperiments in conditional knockout animals lacking either ADAM10 or ADAM17 in leukocytes and cell culture experiments for mechanistic studies. RESULTS: Hospitalised bacterial pneumonia and COVID-19 patients displayed a severity dependent increase of ADAM10 and ADAM17 activity on exosomes. These exosomes caused pathophysiological changes of cardiomyocytes and the endothelial barrier. In a pre-clinical murine pneumonia model, we observed that leukocytes contributed to this increase in exosomal proteolytic activity. In the local environment of the lung, ADAM10 orchestrated a pro-inflammatory response with M1 macrophage polarisation, increased reactive oxygen species (ROS) generation, cytokine release, tissue damage and oedema formation, whereas ADAM17 seemed to dampen the initial inflammatory response to an anti-infective, ROS-balanced level. CONCLUSION: Leukocytic ADAM10 and ADAM17 and their release on exosomes may constitute relevant regulatory elements in bacterial and viral pneumonia, with a potential contribution of exosomes to disease progression and systemic inflammatory responses. Therefore, the diagnostic, prognostic and therapeutic value of ADAM10 and ADAM17 should be evaluated in further preclinical and translational studies, addressing the changes of the immune response and exosomes as cargo vehicles both at local site and for the prevention of systemic effects.