Neutrophil ADAM10 promotes migration and inflammation in ARDS by modulating adhesion and chemokine signaling.

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by excessive neutrophil recruitment, endothelial barrier dysfunction, and persistent inflammation. A Disintegrin and Metalloproteinase 10 (ADAM10) regulates leukocyte trafficking by cleaving adhesion molecules such as VE-cadherin and JAM-A, but its role in neutrophil-driven lung injury remains unclear. We investigated whether neutrophil-derived ADAM10 modulates neutrophil adhesion, migration, and pulmonary inflammation in a murine model of ARDS and assessed the effects of systemic ADAM10 inhibition. Using a neutrophil-specific ADAM10 knockout mouse model (ADAM10^loxP/loxPCatchup-Cre+) and pharmacological ADAM10 inhibition, we evaluated neutrophil recruitment, endothelial permeability, and adhesion molecule expression in lipopolysaccharide (LPS)-induced lung inflammation. Flow cytometry, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were used to assess neutrophil migration, activation, and cytokine release. In vitro adhesion and transmigration assays were performed with human endothelial and epithelial monolayers using freshly isolated human neutrophils. Neutrophil-specific ADAM10 deletion did not affect endothelial permeability but reduced neutrophil recruitment into the alveolar space, associated with decreased CXCL1 and CXCL2/3 secretion and increased CD44 surface expression. ADAM10 inhibition enhanced adhesion but impaired transmigration, mirroring genetic deletion. Systemic inhibition also suppressed neutrophil activation and inflammatory cytokine release. Neutrophil ADAM10 promotes neutrophil migration and inflammation in ARDS by modulating chemokine signaling and adhesion molecule expression. Systemic ADAM10 inhibition reduces neutrophil infiltration and inflammatory cytokine production, suggesting ADAM10 as a potential therapeutic target to mitigate neutrophil-driven lung injury.