Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
Catharina Conrad, Daniela Yildiz, Simon J. Cleary, Andreas Margraf, Lena Cook, Uwe Schlomann, Barry Panaretou, Jessica L. Bowser, Harry Karmouty-Quintana, Jiwen Li, Nathaniel K. Berg, Samuel C. Martin, Ahmad Aljohmani, S. Farshid Moussavi-Harami, Kristin M. Wang, Jennifer J. Tian, Mélia Magnen, Colin Valet, Longhui Qiu, Jonathan P. Singer, Holger K. Eltzschig, CAPSys Study Group, Wilhelm Bertrams, Susanne Herold, Norbert Suttorp, Bernd Schmeck, Zachary T. Ball, Alexander Zarbock, Mark R. Looney, Jörg W. Bartsch
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