Over the past 50 years, steady growth in the field of metalloproteinase biology has shown that the degradation of extracellular matrix components represents only a fraction of the functions performed by these enzymes and has highlighted their fundamental roles in immunity. Metalloproteinases regulate aspects of immune cell development, effector function, migration and ligand-receptor interactions. They carry out ectodomain shedding of cytokines and their cognate receptors. Together with their endogenous inhibitors TIMPs (tissue inhibitor of metalloproteinases), these enzymes regulate signalling downstream of the tumour necrosis factor receptor and the interleukin-6 receptor, as well as that downstream of the epidermal growth factor receptor and Notch, which are all pertinent for inflammatory responses. This Review discusses the metalloproteinase family as a crucial component in immune cell development and function.

Hematopoietic stem cells (HSCs) self-renew or differentiate into blood cell lineages following extrinsic cues propagated in specialized niches. Support cells and soluble factors in the niche respond to stress and enable progenitor activity. Metalloproteases (MMPs, ADAMs, ADAMTSs) and their inhibitors (TIMPs) control certain physical and biochemical features of the niche by altering protease-dependent bioavailability of local niche factors (e.g., CXCL12, SCF, TGFb, VEGF), matrix turnover, and cellular interactions. With over 40 examples of diverse metalloprotease substrates known to trigger fate-changing decisions, the spatially confined activity of this multi-member protease family is ideally positioned to constitute a higher order control over hematopoiesis. Comprehension of regulated proteolysis in the bone marrow may fuel innovative strategies to harness HSC fate and function. Metalloproteases Can Orchestrate Physical and Biochemical Cues for Mammalian HematopoiesisHSCs are the only cells able to reconstitute all blood cell lineages. HSCs reside in a niche that provides instructions for self-renewal or the signals to develop into specific progenitors. The niche serves as a physical address (perivascular bone marrow for most adult HSC) and comprises various entities, including support cells (macrophages, megakaryocytes, osteoblasts, endothelial, perivascular, and specialized reticular cells), the extracellular matrix (ECM; comprising structural collagens, fibronectin, and laminin), local growth factors and cytokines, shear forces of circulation, oxygen tension, and sympathetic innervation [1-3]. These features create a discrete environment for the quiescence and maintenance of the HSC pool or proliferation and differentiation into progenitors, which give rise to all effector blood cells during homeostasis and following stress (e.g., pregnancy, anemia, infection, and irradiation). In both mice and humans, the initial location of hematopoietic cells is the early embryonic yolk sac and aorta-gonad-mesonephros; they subsequently reside in the embryonic liver before taking up residence in the bone marrow (BM) [4]. The spleen and liver provide additional poststress sites of hematopoiesis for mobilized HSCs in the adult. Most HSCs are perivascular in the BM, with other cellular players providing support through cell-cell contact or delivery of soluble factors (detailed elsewhere) [1,2].Along with structural and physical properties of the ECM shaping the niche, the ECM is a growth factor-rich scaffold that mediates many of the extracellular interactions. Multiple aspects of the niche entities are subject to regulation by metalloproteases and their natural inhibitors. Metalloproteases are the largest of the five groups of proteases in the human genome (Box 1), where metzincins have a zinc at the active site and include enzymes such as matrix metalloproteases (MMPs), a disintegrin and metalloproteases (ADAMs), and ADAM with thrombospondin motifs (ADAMTSs); these are inhibited by tissue inhibitors of metalloproteases (TIM...