In sum, these data suggest that the increase in MMP-12 in Trpml3-/- BALF is the major driving force of the emphysema phenotype, caused by a combination of endocytosis and trafficking defects in the early endosomal pathway of AMΦ, leading to a backlog and congestion in the system and likely a reduced delivery of endocytosed MMP-12 to lysosomes for degradation. Here, MMP12 is linked to pulmonary emphysema.