Pro‐Angiogenic Capacity of MMP‐9 Produced by Different Types of Inflammatory Leukocytes is Determined by the Levels of TIMP‐1 Complexed with the MMP‐9 Proenzyme

Abstract

By delivering a potent matrix metalloproteinase, MMP‐9, inflammatory neutrophils and macrophages (mε) play an important role in tumor angiogenesis. We have previously demonstrated that uniquely high angiogenic capacity of neutrophil MMP‐9 (nMMP‐9) is determined by its TIMP‐free status. Herein, we compared biochemically and functionally nMMP‐9 with the MMP‐9 produced by monocytic cells, including monocytes and innate (M0), tumor suppressing (M1), and tumor promoting (M2) macrophages (mε). Angiogenic potential of a specific inflammatory leukocyte type was related to gene and protein expression levels of TIMP‐1 and MMP‐9, ultimately determining how much TIMP‐1 is complexed with secreted MMP‐9. Resembling neutrophils that release TIMP‐free MMP‐9, M2 mε produce MMP‐9 complexed with very low amounts of TIMP‐1. Correspondingly, M2 mε induced relatively high levels of neovascularization, yielding only to neutrophils in their angiogenic potential. Low TIMP‐1/MMP‐9 ratios inversely correlated with the high proteolytic activity of nMMP‐9 and M2 mε MMP‐9 in a substrate cleavage assay. Finally, the lack of TIMP‐1 in nMMP‐9 and low TIMP‐1 burden in M2 mε MMP‐9 were functionally linked to their high capacity to induce new blood vessel formation, thereby highlighting a biochemical mechanism underlying unique angiogenic potential of MMP‐9 delivered by inflammatory neutrophils and pro‐tumorigenic macrophages.