A disintegrin and metalloproteinase domain-15 deficiency leads to exaggerated cigarette smoke-induced chronic obstructive pulmonary disease (COPD)-like disease in mice

A disintegrinandmetalloproteinase domain-15 (ADAM15) is expressed by cells implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD), but its contributions to COPD are unknown. To address this gap, ADAM15 levels were measured in samples from cigarette smoke (CS)-versus air-exposed wild-type (WT) mice. CS-induced COPD-like disease was compared in CS-exposed WT,Adam15(-/-), andAdam15bone marrow chimeric mice. CS exposure increased Adam15 expression in lung macrophages and CD8(+)T cells and to a lesser extent in airway epithelial cells in WT mice. CS-exposedAdam15(-/-)mice had greater emphysema, small airway fibrosis, and lung inflammation (macrophages and CD8(+)T cells) than WT mice.Adam15bone marrow chimera studies revealed thatAdam15deficiency in leukocytes led to exaggerated pulmonary inflammation and COPD-like disease in mice.Adam15deficiency in CD8(+)T cells was required for the exaggerated pulmonary inflammation and COPD-like disease in CS-exposedAdam15(-/-)mice (as assessed by genetically deleting CD8(+)T cells inAdam15(-/-)mice).Adam15deficiency increased pulmonary inflammation by rendering CD8(+)T cells and macrophages resistant to CS-induced activation of the mitochondrial apoptosis pathway by preserving mTOR signaling and intracellular Mcl-1 levels in these cells. These results strongly link ADAM15 deficiency to the pathogenesis of COPD.