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ADAM8 signaling drives neutrophil migration and ARDS severity
Catharina Conrad, … , Mark R. Looney, Jörg W. Bartsch
Catharina Conrad, … , Mark R. Looney, Jörg W. Bartsch
Published February 8, 2022
Citation Information: JCI Insight. 2022;7(3):e149870. https://doi.org/10.1172/jci.insight.149870.
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Research Article Inflammation Pulmonology

ADAM8 signaling drives neutrophil migration and ARDS severity

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Abstract

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.

Authors

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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Figure 1

Genetic deletion and pharmacological inhibition of Adam8 impair neutrophil motility in vivo.

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Genetic deletion and pharmacological inhibition of Adam8 impair neutroph...
(A) Schema for cremaster IVM after i.sc. TNF-α. (B) Number of cells adherent to endothelium, (C) rolling velocities, and (D) quantification of transmigrated Adam8−/− and Adam8+/+ neutrophils (right). Representative fields showing leukocyte extravasation (left); arrow indicates direction of emigration. Scale bar, 25 μm. Data for B–D are shown as mean ± SD. **, P < 0.005; Student’s t test. (E) Schema for ADAM8 inhibitor experiments after i.t. LPS. (F) BAL neutrophils and cytospins (left); scale bar, 25 μm. (G) BAL MPO ELISA. (H) Quantification of lung tissue and peripheral blood neutrophils. Data for F–H are mean ± SD. *, P < 0.05; **, P < 0.01; ***, P < 0.001; 2-way ANOVA followed by Holm-Šídák multiple-comparison test. (I) Immunostaining of neutrophils (S100A8, green) in 100 μm lung sections. *, large airways. Scale bar, 2 mm. (J) Quantification and (K) representative images of intravascular (red) and total (green) neutrophils in lung sections at baseline and after i.t. LPS + BK1361 or CP. Ly6G antibody was injected i.v. 10 minutes prior to euthanasia to label intravascular neutrophils; total lung neutrophils were visualized by S100A8 staining (green) and nuclei by DAPI (blue). Neutrophils were quantified from 7 fields/animal (n = 5). Data in J are mean ± SD, 2-way ANOVA followed by Holm-Šídák multiple comparison test; LPS+CP vs. LPS+BK1361 (P = 0.0025); LPS+CP vs. PBS (P = 0.008); LPS+BK1361 vs. PBS (NS). Scale bar, 100 μm (K). (L) Two-photon lung IVM of MRP8-Cre mTmG mice + BK1361 or CP 3 hours after LPS challenge. Representative images of neutrophil influx (MRP8+, green). Arrowheads, neutrophil cluster. Scale bar, 50 μm. (M) Quantification of neutrophils circulating (track duration < 60 s, left graph) and migrating (track duration > 60 s, right graph) through the lung, n = 3. Blue, baseline; gray, LPS+BK1361; black, LPS+CP. **, P < 0.01; 2-way ANOVA. i.sc., intrascrotal injection.

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