title: Angiogenic capacity of M1- and M2-polarized macrophages is determined by the levels of TIMP-1 complexed with their secreted proMMP-9.
abstract: A proangiogenic function of tissue-infiltrating monocytes/macrophages has long been attributed to their matrix metalloproteinase-9 zymogen (proMMP-9). Herein, we evaluated the capacity of human monocytes, mature M0 macrophages, and M1- and M2-polarized macrophages to induce proMMP-9-mediated angiogenesis. Only M2 macrophages induced angiogenesis at levels comparable with highly angiogenic neutrophils previously shown to release their proMMP-9 in a unique form, free of tissue inhibitor of metalloproteinases-1 (TIMP-1). Macrophage differentiation was accompanied by induction of low-angiogenic, TIMP-1-encumbered proMMP-9. However, polarization toward the M2, but not the M1 phenotype, caused a substantial downregulation of TIMP-1 expression, resulting in production of angiogenic, TIMP-deficient proMMP-9. Correspondingly, the angiogenic potency of M2 proMMP-9 was lost after its complexing with TIMP-1, whereas TIMP-1 silencing in M0/M1 macrophages rendered them both angiogenic. Similar to human cells, murine bone marrow-derived M2 macrophages also shut down their TIMP-1 expression and produced proMMP-9 unencumbered by TIMP-1. Providing proof that angiogenic capacity of murine M2 macrophages depended on their TIMP-free proMMP-9, Mmp9-null M2 macrophages were nonangiogenic, although their TIMP-1 was severely downregulated. Our study provides a unifying molecular mechanism for high angiogenic capacity of TIMP-free proMMP-9 that would be uniquely produced in a pathophysiological microenvironment by influxing neutrophils and/or M2 polarized macrophages.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Zajac
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schweighofer
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Kupriyanova
authors.forename: Anna
authors.initials: A
authors.lastname: Juncker-Jensen
authors.forename: Petra
authors.initials: P
authors.lastname: Minder
authors.forename: James P
authors.initials: JP
authors.lastname: Quigley
authors.forename: Elena I
authors.initials: EI
authors.lastname: Deryugina
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002642:Chick Embryo; D015536:Down-Regulation / Q000502:physiology; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004792:Enzyme Precursors; C560822:TIMP1 protein, human; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9