Identification of a lepidopteran matrix metalloproteinase with dual roles in metamorphosis and innate immunity

Matrix metalloproteinases (MMPs) are key enzymes in mammalian tissue remodeling and inflammation. Recently, we postulated that an endogenous MMP expressed in the lepidopteran model Galleria mellonella during metamorphosis causes degradation of collagen-IV, which in turn results in activation of innate immunity. Here, we report that degradation of collagen-IV by hemocytes is enhanced upon injection of bacterial lipopolysaccharide (LPS), and that this activity is sensitive to the MMP-inhibitor GM6001. Therefore, we screened for enzymes behind this activity and identified the first MMP from Lepidoptera (Gm1-MMP), and the third from insects. Gm1-MMP shares homology with the first MMP from Drosophila (Dm1-MMP) known to be essential for tissue remodeling during metamorphosis. Using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis, we confirmed up-regulation of Gm1-MMP expression after pupation, when extracellular matrix breakdown of larval tissues occurs. In addition, we determined that LPS challenge induces Gm1-MMP expression in hemocytes, implicating its participation in collagen-IV degradation upon septic injury. These results suggest dual roles of Gm1-MMP in innate immunity and metamorphosis. Interestingly, our phylogenetic analysis elucidates that Gm1-MMP share highest similarity with human MMP-19 and MMP-28, whose functions in mammalian wounding and inflammatory response have recently been demonstrated; hence, the present findings may provide insights into the evolutionarily conserved features of MMPs.