Metalloproteinases: a Functional Pathway for Myeloid Cells

MMP structure and expression in myeloid cells. (Top) MMPs have a basic structure composed of functional subdomains. All MMPs have a “minimal domain” comprising an amino-terminal signal sequence that directs them to the endoplasmic reticulum, a propeptide domain with a cysteine that provides a zinc-interacting thiol (SH) group to maintain them as inactive zymogens, and a catalytic domain with three histidines that form a zinc-binding site (Zn). Most MMPs contain additional domains, the most common of which is the carboxy-terminal HPX-like domain, which mediates interactions with TIMPs, cell surface molecules, and proteolytic substrates. This domain is composed of a four-β-propeller structure and contains a disulfide bond (S-S) between the first and the last subdomains. MT-MMPs have an additional single-span transmembrane domain (TM) and a very short cytoplasmic domain (Cy). (Bottom) Expression of MMPs in myeloid cells. Neutrophils and macrophages release a variety of proteinases into the extracellular space during diverse biological processes including infection, tumorigenesis, and tissue repair. While neutrophils and macrophages are able to express several MMPs, the specific MMPs expressed by each cell type depend on the tissue microenvironment. In addition, both neutrophils and macrophages express a number of ADAM and ADAMTS proteins (not depicted here) that are important for their function and for regulating inflammation and signaling.

Functions of MMP12 and MMP9 in biological processes. MMP12 and MMP9 have contrasting roles in the processes of inflammation, angiogenesis, and metastasis, with MMP12 inhibiting these processes and MMP9 promoting them. MMP12 protects against inflammation by cleaving complements C3 and C4b and reducing complement activation, cleaving complements C3a and C5a and reducing neutrophil recruitment, and creating cleaved forms of C3b and iC3b that are potent phagocytosis enhancers ( 65 ). In contrast, MMP9 promotes inflammation by stimulating macrophage migration and infiltration upon being activated by plasminogen ( 66 ). MMPs also promote autoimmune disease. For example, in the skin disease bullous pemphigoid, MMP9 activated by plasmin proteolytically inactivates α1-proteinase inhibitor (α1-PI), the physiological inhibitor of neutrophil elastase (NE), which allows unrestrained activity of NE ( 67 ). NE degrades BP180, which results in dermal-epidermal separation ( 68 , 69 ). MMP12 inhibits angiogenesis through its cleavage of plasminogen to generate angiostatin, which results in decreased endothelial cell proliferation ( 70 ). MMP9, however, promotes angiogenesis through the release of VEGF into the extracellular matrix following activation by plasmin or upon secretion from TIMP-free neutrophils ( 27 , 50 ). Lung metastatic growth is reduced by MMP12 produced by tumor-associated macrophages, which interact with chemokines to decrease tumor-associated microvessel density ( 58 ). Lung metastasis is increased by MMP9 produced by tumor-associated macrophages via VEGFR-1/Flt-1 tyrosine kinase, and MMP9 levels in the lungs of patients with distant tumors are significantly elevated compared with the lungs of control patients ( 71 ). Finally, in addition to the above functions, MMP12 has direct antimicrobial activity through its HPX domain by disrupting bacterial membranes in phagolysosomes ( 42 ). MMP12 also enhances antiviral clearance by binding to the promoter of the gene encoding IκBα (NFKBIA) and enhancing the production of IκBα, which promotes IFN-α secretion from the cell ( 43 ). Together, these examples illustrate the diverse functions of MMPs in myeloid cells.