Expression array of Mt1-mmp+/+ and Mt1-mmp-/- mouse macrophages in response to LPS or IL-4

Macrophages dominate inflammatory environments where they modify the extracellular matrix by mobilizing complex repertoires of proteolytic enzymes. Nevertheless, the dominant proteinases used by macrophage as they confront physiologic tissue barriers remain undefined. Herein, we have characterized the molecular mechanisms that define human macrophage-extracellular matrix interactions ex vivo. Resting and immune-polarized macrophages are shown to proteolytically remodel basement membranes while infiltrating the underlying interstitial matrix. In an unbiased screen to identify key proteases, we find that the macrophage metalloproteinase, MT1-MMP, is the dominant effector of basement membrane degradation and invasion. These studies not only identify MT1-MMP as a key proteolytic effector of extracellular matrix remodeling by human macrophages, but also define the invasive strategies used by macrophages to traverse physiologic tissue barriers. Primary mouse bone marrow derived macrophages from global knockout [Mt1-mmp(-/-)] mice and wild-type [Mt1-mmp(+/+)] littermates on an outbred Swiss Black background were cultured for 24 hours in the presence of growth media alone or supplemented with 1ug/ml LPS or 20ng/ml IL-4 and harvested for RNA extraction and hybridization on Affymetrix microarrays.