Trends in Immunology
ReviewClipping, shedding and RIPping keep immunity on cue
Introduction
Proteolytic processing at the cell surface and in the pericellular environment by metalloproteinases is emerging as an intriguing and novel level of control for the immune system. Immune function depends on a series of events that activate and amplify the reaction targeted at the antigen, and proteolytic systems are central to all of these events. Recent studies have firmly established the importance of proteolytic regulation of processes associated with both innate immunity, which provides the first line of defense against invading pathogens, and adaptive immunity, which affords long-term protection via the generation of memory against specific foreign antigens. Two important families involved are the matrix metalloproteinases (MMPs) and the disintegrin metalloproteinases (ADAMs) (Box 1). Metalloproteinase involvement in aspects of immune-cell migration 1, 2, membrane protein ectodomain shedding [3], and cytokine and chemokine function [4] has been recently reviewed. Here, we focus on how ADAMs and MMPs act as regulatory triggers of lymphocyte maturation, clonal expansion, migration, and effector functions.
Metalloproteinases located on the plasma membrane, either as transmembrane proteins or anchored to cell-surface molecules, serve as activators or inhibitors of immune mediators. This is achieved through several types of proteolytic processing, including clipping of low-molecular weight chemokines or by ‘sheddase’ activity, which releases an intact ectodomain of the target cell-surface molecule (Box 2). Sheddases can also act in combination with intracellular γ-secretases to perform RIPping of the remaining membrane-associated protein (Box 2). In the context of immunity, the cell-surface localization of proteolysis is ideal for the rapid processing and delivery of already-synthesized instructive signals such as cytokines or chemokines. Proteolytic cleavage is also essential for generating soluble stimuli to initiate a systemic immune response, although subsequent receptor shedding from the cell surface through metalloproteinase activity is also a mode for dampening the initiated response. The production of chemokine gradients is a crucial early step in the immune response [4], and extracellular proteases shed membrane chemokines or modify (clip) soluble chemokines to alter their localization patterns and activity to direct immune-cell migration to the site of injury [5]. In addition, proteolytic processing plays an important role in activating signal transduction pathways essential for lymphocyte development, such as that of T cells 6, 7.
Metalloproteinases are kept in check by tissue inhibitors of metalloproteinases (TIMPs) in the extracellular milieu (Box 1). Whereas little is known about the immunological consequences of altered TIMP activity, deficiency of specific murine TIMPs impacts inflammation in several models. For instance, shedding of tumor necrosis factor (TNF) by ADAM17 is an early step in both systemic and local inflammation: serum TNF levels are known to regulate components of the adaptive immune system as well as to affect target tissues. TIMP3 is the physiological inhibitor of ADAM17, and Timp3−/− mice exhibit elevated soluble TNF levels accompanied by an enhanced potential for inflammation in several tissues 8, 9, 10. Thus, many examples are continually emerging in which metalloproteinases and their specific inhibitors actively participate in various aspects of immunity.
Section snippets
Metalloproteinases facilitate lymphocyte development and proliferation
Lymphopoiesis begins in the bone marrow, where B- and T-lymphocyte precursors are generated. T-cell progenitors migrate to the thymus, and a cascade of interactions between immature thymocytes and the thymic stroma produces mature T lymphocytes, which then migrate to peripheral lymphoid tissues 11, 12. In the spleen or lymph nodes, mature T lymphocytes encounter foreign antigen-MHC complexes on the surface of antigen presenting cells (dendritic cells, macrophages, activated B cells), and an
Myeloid and lymphoid cell migration is dependent on metalloproteinase activity
One of the earliest responses upon acute and chronic inflammation is that of leukocyte recruitment to the site of infection. Polymorphonuclear leukocytes (PMNs) are among the first immune cells to arrive, and they set the stage for innate as well as adaptive immunity. Significant knowledge has accumulated on the importance of generating chemokine and cytokine gradients for immune-cell recruitment, and the clipping performed by metalloproteinases is an emerging paradigm for this step. Chemokines
Humoral immunity
Chemokine and cytokine signaling is central to initiating an adequate humoral response. TNF is a potent proinflammatory cytokine, and many of its paracrine and endocrine functions require shedding of its cell-membrane-bound form by ADAM17 [16]. Curiously, ADAM17 also regulates the levels of the receptors TNFR1 and TNFR2 by cleaving them from the cell surface to generate soluble antagonists 40, 41 (Figure 2a). Bacteria have been found to induce ADAM17, either through direct activation of the
Conclusions
Proteolytic processing through clipping, shedding, and RIPping affects a vareity of substrates that are crucial throughout immunity. These encompass cytokines and their receptors, chemokines and their adaptors, extracellular components of cell-mediated and humoral immunity, matrix proteins, cell-adhesion molecules, as well as those linked to tumor immunity (Box 3). Because proteases are involved in all aspects of an immune response – from development, expansion, effector function, to
Acknowledgements
The authors apologize to the many laboratories whose relevant work was not cited here due to space restraints. We thank Dr. Paul Waterhouse for critical reading of the manuscript. G.M. is supported by Cancer Research, UK; Medical Research Council, UK; and Biotechnology and Biochemical Sciences Council, UK. R.K. is supported by the Canadian Institutes of Health Research.
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