Matrix metalloproteinases as modulators of inflammation and innate immunity

Key Points

  • Inflammation comprises the detection and response to injury and pathogens, the accumulation and intervention of cells that eliminate invading microorganisms and infected host cells, and the repair of tissues that are damaged by the initial insult, trauma or the responses of the host.

  • Numerous effector proteins regulate and coordinate repair, leukocyte recruitment, and immunity, and the activity of many of these effectors is controlled by limited proteolysis. So, proteinases provide an important control that regulates the varied cellular processes defining inflammation.

  • Matrix metalloproteinases (MMPs) constitute a family of 24 mammalian extracellular or membrane-bound proteinases that function in wound repair, mucosal defence, inflammation and acquired immunity. MMPs accomplish these varied tasks by acting on a variety of protein substrates, such as antimicrobial peptides, adhesion proteins, receptors, cytokines, chemokines and extracellular-matrix proteins.

  • In particular, several MMPs regulate the activity of chemokines, either directly or indirectly, thereby controlling many aspects of inflammation and immunity. Many chemokines are directly cleaved by MMPs, thereby resulting in enhancement, inactivation or antagonism of chemokine activities. By contrast, others chemokines are regulated by MMP cleavage of substrates that bind, retain and concentrate the chemotactic molecules in particular locations: that is, they establish chemokine gradients. This results in a coordinated influx of immune effector cells, including neutrophils, monocytes and eosinophils. So, MMPs actively participate in the evolution and outcome of the inflammatory response.

  • MMP7 is used as an example of an MMP that has diverse functions in the innate immune response. In the gut, MMP7 participates in the barrier function of the epithelium by activating antimicrobial peptides. In response to epithelial injury, MMP7 is expressed by cells at the wound edge, and its activity is required for re-epithelialization. This is thought to occur through the shedding of epithelial (E)-cadherin ectodomains, which loosen cell–cell contacts. Furthermore, at the wound site, MMP7 sheds chemokine-bound syndecan-1, a transmembrane proteoglycan, which in turn guides the transepithelial influx of neutrophils.

Abstract

As their name implies, matrix metalloproteinases are thought to be responsible for the turnover and degradation of the extracellular matrix. However, matrix degradation is neither the sole nor the main function of these proteinases. Indeed, as we discuss here, recent findings indicate that matrix metalloproteinases act on pro-inflammatory cytokines, chemokines and other proteins to regulate varied aspects of inflammation and immunity.

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Figure 1: Domain structure of the mammalian MMP family.
Figure 2: Minimal components of the proteolytic process.
Figure 3: Mucosal immunity.
Figure 4: MMPs in inflammation in response to tissue injury.

References

  1. 1

    Velasco, G. et al. Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J. Biol. Chem. 274, 4570–4576 (1999).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Bode, W., Gomis-Ruth, F. X. & Stockler, W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the 'metzincins'. FEBS Lett. 331, 134–140 (1993).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Massova, I., Kotra, L. P., Fridman, R. & Mobashery, S. Matrix metalloproteinases: structures, evolution, and diversification. FASEB J. 12, 1075–1095 (1998).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Shapiro, S. D. Matrix metalloproteinase degradation of extracellular matrix: biological consequences. Curr. Opin. Cell Biol. 10, 602–608 (1998).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Van Wart, H. E. & Birkedal-Hansen, H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc. Natl Acad. Sci. USA 87, 5578–5582 (1990).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Strongin, A. Y. et al. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J. Biol. Chem. 270, 5331–5338 (1995).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Hernandez-Barrantes, S. et al. Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation. J. Biol. Chem. 275, 12080–12089 (2000).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Wang, Z., Juttermann, R. & Soloway, P. D. TIMP-2 is required for efficient activation of proMMP-2 in vivo. J. Biol. Chem. 275, 26411–26415 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9

    Caterina, J. J. et al. Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2 (Timp-2) gene alters proMMP-2 activation. J. Biol. Chem. 275, 26416–26422 (2000).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Yang, Z., Strickland, D. K. & Bornstein, P. Extracellular matrix metalloproteinase 2 levels are regulated by the low density lipoprotein-related scavenger receptor and thrombospondin 2. J. Biol. Chem. 276, 8403–8408 (2001).

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Barmina, O. Y. et al. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization. J. Biol. Chem. 274, 30087–30093 (1999).

    CAS  PubMed  Article  Google Scholar 

  12. 12

    Weiss, S. J., Peppin, G., Ortiz, X., Ragsdale, C. & Test, S. T. Oxidative autoactivation of latent collagenase by human neutrophils. Science 227, 747–749 (1985).

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Peppin, G. J. & Weiss, S. J. Activation of the endogenous metalloproteinase, gelatinase, by triggered human neutrophils. Proc. Natl Acad. Sci. USA 83, 4322–4326 (1986).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Fu, X., Kassim, S. Y., Parks, W. C. & Heinecke, J. W. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J. Biol. Chem. 276, 41279–41287 (2001).

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002).

    CAS  PubMed  Article  Google Scholar 

  16. 16

    Fu, X., Kassim, S. Y., Parks, W. C. & Heinecke, J. W. Hypochlorous acid generated by myeloperoxidase modifies adjacent tryptophan and glycine residues in the catalytic domain of matrix metalloproteinase-7 (matrilysin): an oxidative mechanism for restraining proteolytic activity during inflammation. J. Biol. Chem. 278, 28403–28409 (2003). References 12–16 show that reactive metabolites, often leukocyte-generated oxidants, can both activate and inactivate the catalytic activity of MMPs. Although these mechanisms have not yet been shown in vivo , they are probably important for the regulation of MMPs in inflammation.

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18

    Mackay, A. R., Hartzler, J. L., Pelina, M. D. & Thorgeirsson, U. P. Studies on the ability of 65-kDa and 92-kDa tumor cell gelatinases to degrade type IV collagen. J. Biol. Chem. 265, 21929–21934 (1990).

    CAS  PubMed  Google Scholar 

  19. 19

    Halpert, I. et al. Matrilysin is expressed by lipid-laden macrophages at sites of potential rupture in atherosclerotic lesions and localizes to areas of versican deposition, a proteoglycan substrate for the enzyme. Proc. Natl Acad. Sci. USA 93, 9748–9753 (1996).

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Brooks, P. C. et al. Localization of matrix metalloproteinase MMP-2 to the surface of invasive cells by interaction with integrin αvβ3 . Cell 85, 683–693 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Dumin, J. A. et al. Procollagenase-1 (matrix metalloproteinase-1) binds the integrin α2β1 upon release from keratinocytes migrating on type I collagen. J. Biol. Chem. 276, 29368–29374 (2001).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Stricker, T. P. et al. Structural analysis of the α2 integrin I domain/procollagenase-1 (matrix metalloproteinase-1) interaction. J. Biol. Chem. 276, 29375–29381 (2001).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Yu, Q. & Stamenkovic, I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-β and promotes tumor invasion and angiogenesis. Genes Dev. 14, 163–176 (2000).

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Yu, W. H. & Woessner, J. F. Jr. Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J. Biol. Chem. 275, 4183–4191 (2000).

    CAS  PubMed  Article  Google Scholar 

  25. 25

    Yu, W. H., Woessner, J. F. Jr, McNeish, J. D. & Stamenkovic, I. CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling. Genes Dev. 16, 307–323 (2002). This paper provides a good example of how a 'secreted' MMP is bound to and compartmentalized by a cell-surface molecule.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Gross, J. & Lapiere, C. M. Collagenolytic activity in amphipian tissues: a tissue culture assay. Proc. Natl Acad. Sci. USA 48, 1014–1022 (1962).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    McQuibban, G. A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000). This paper shows how exosite scanning and yeast two-hybrid techniques can be used to identify novel MMP substrates: in this case, chemokines. Together with other studies by these investigators (references 54 and 55), this study provides evidence that MMP proteolysis directly regulates chemokine activity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Guo, L. et al. A proteomic approach for the identification of cell-surface proteins shed by metalloproteases. Mol. Cell. Proteomics 1, 30–36 (2002).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Tam, E. M., Morrison, C. J., Wu, Y. I., Stack, M. S. & Overall, C. M. Membrane protease proteomics: isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc. Natl Acad. Sci. USA 101, 6917–6922 (2004). This paper describes a proteomics study using state-of-the-art technology to identify MMP substrates. This knowledge is essential for understanding the function of these enzymes in vivo.

    CAS  PubMed  Article  Google Scholar 

  30. 30

    McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: they're not just for matrix anymore! Curr. Opin. Cell Biol. 13, 534–540 (2001).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl Acad. Sci. USA 97, 4052–4057 (2000).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Hotary, K., Allen, E., Punturieri, A., Yana, I. & Weiss, S. J. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2, and 3. J. Cell Biol. 149, 1309–1323 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Hotary, K. B. et al. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J. Exp. Med. 195, 295–308 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35

    Filippov, S. et al. Matrilysin-dependent elastolysis by human macrophages. J. Exp. Med. 198, 925–935 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Opdenakker, G., Van den Steen, P. E. & Van Damme, J. Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol. 22, 571–579 (2001).

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Lee, H. M. et al. Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinase inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal anti-inflammatory drug. J. Periodontol. 75, 453–463 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Whelan, C. J. Metalloprotease inhibitors as anti-inflammatory agents: an evolving target? Curr. Opin. Investig. Drugs 5, 511–516 (2004).

    CAS  PubMed  Google Scholar 

  40. 40

    Sierevogel, M. J., Pasterkamp, G., de Kleijn, D. P. & Strauss, B. H. Matrix metalloproteinases: a therapeutic target in cardiovascular disease. Curr. Pharm. Des. 9, 1033–1040 (2003).

    CAS  PubMed  Article  Google Scholar 

  41. 41

    Itoh, T. et al. The role of matrix metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. J. Immunol. 169, 2643–2647 (2002).

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Mudgett, J. S. et al. Susceptibility of stromelysin 1-deficient mice to collagen-induced arthritis and cartilage destruction. Arthritis Rheum. 41, 110–121 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Parks, W. C. Matrix metalloproteinases in repair. Wound Repair Regen. 7, 423–432 (1999).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Pilcher, B. K. et al. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J. Cell Biol. 137, 1445–1457 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Dunsmore, S. E. et al. Matrilysin expression and function in airway epithelium. J. Clin. Invest. 102, 1321–1331 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    McGuire, J. K., Li, Q. & Parks, W. C. Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am. J. Pathol. 162, 1831–1843 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47

    Legrand, C. et al. Airway epithelial cell migration dynamics: MMP-9 role in cell–extracellular matrix remodeling. J. Cell Biol. 146, 517–529 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48

    Betsuyaku, T., Fukuda, Y., Parks, W. C., Shipley, J. M. & Senior, R. M. Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. Am. J. Pathol. 157, 525–535 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Saarialho-Kere, U. K., Crouch, E. C. & Parks, W. C. Matrix metalloproteinase matrilysin is constitutively expressed in human exocrine epithelium. J. Invest. Dermatol. 105, 190–196 (1995).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Ouellette, A. J. & Selsted, M. E. Paneth cell defensins: endogenous peptide components of intestinal host defense. FASEB J. 10, 1280–1289 (1996).

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Wilson, C. L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999). This study identifies α-defensins as a new class of substrates for MMPs and demonstrates a specific role for MMP7 in innate immunity.

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Mulvey, M. A. et al. Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282, 1494–1497 (1998).

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Powell, W. C., Fingleton, B., Wilson, C. L., Boothby, M. & Matrisian, L. M. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr. Biol. 9, 1441–1447 (1999). This study establishes that FASL is a substrate for MMP7. MMP-mediated apoptosis, through the activation of FASL, might provide a mechanism for bacterial clearance, as indicated in figure 4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Hartzell, W. & Shapiro, S. D. Macrophage elastase prevents Gemella morbillorum infection and improves outcome following murine bone marrow transplantation. Chest 116, 31S–32S (1999).

    CAS  PubMed  Article  Google Scholar 

  55. 55

    López-Boado, Y. S. et al. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J. Cell Biol. 148, 1305–1315 (2000).

    PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    López-Boado, Y. S., Wilson, C. L. & Parks, W. C. Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin. J. Biol. Chem. 276, 41417–41423 (2001).

    PubMed  Article  Google Scholar 

  57. 57

    Wilson, C. L. & Matrisian, L. M. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int. J. Biochem. Cell Biol. 28, 123–136 (1996).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Kagnoff, M. F. & Eckmann, L. Epithelial cells as sensors for microbial infection. J. Clin. Invest. 100, 6–10 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Borish, L. C. & Steinke, J. W. Cytokines and chemokines. J. Allergy Clin. Immunol. 111, S460–S475 (2003).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    McQuibban, G. A. et al. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 100, 1160–1167 (2002).

    CAS  PubMed  Google Scholar 

  61. 61

    McQuibban, G. A. et al. Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J. Biol. Chem. 276, 43503–43508 (2001).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Van den Steen, P. E., Proost, P., Wuyts, A., Van Damme, J. & Opdenakker, G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood 96, 2673–2681 (2000).

    CAS  PubMed  Google Scholar 

  63. 63

    Van Den Steen, P. E. et al. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activities. Eur. J. Biochem. 270, 3739–3749 (2003).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Corry, D. B. et al. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nature Immunol. 3, 347–353 (2002). One the first papers to show that MMPs establish chemokine gradients in vivo . Reference 71 is a follow-up to these studies.

    CAS  Article  Google Scholar 

  65. 65

    Pruijt, J. F. et al. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc. Natl Acad. Sci. USA 96, 10863–10868 (1999).

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002). This paper describes a mechanism in which three epithelial products — an MMP, a CXC-chemokine and a proteoglycan — interact to control and coordinate acute inflammation at sites of injury.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67

    Zhang, K. et al. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nature Neurosci. 6, 1064–1071 (2003). This interesting study shows that MMP2 secreted by HIV-infected macrophages cleaves CXCL12 to generate a potent neurotoxin.

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Balbin, M. et al. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nature Genet. 35, 252–257 (2003).

    CAS  PubMed  Article  Google Scholar 

  69. 69

    Khandaker, M. H. et al. Metalloproteinases are involved in lipopolysaccharide- and tumor necrosis factor-α-mediated regulation of CXCR1 and CXCR2 chemokine receptor expression. Blood 93, 2173–2185 (1999).

    CAS  PubMed  Google Scholar 

  70. 70

    Li, X. Y., Donaldson, K., Brown, D. & Macnee, W. The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation. Am. J. Resp. Cell Mol. Biol. 13, 185–195 (1995).

    CAS  Article  Google Scholar 

  71. 71

    Corry, D. B. et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J. 18, 995–997 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Haro, H. et al. Matrix metalloproteinase-3-dependent generation of a macrophage chemoattractant in a model of herniated disc resorption. J. Clin. Invest. 105, 133–141 (2000). Together with reference 102, this paper shows that specific MMPs function as crucial components of an inflammatory network between different cell types, using a model of tissue resorption.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    Hautamaki, R. D., Kobayashi, D. K., Senior, R. M. & Shapiro, S. D. Requirement for macrophage elastase for cigarette smoke-induced emphysema. Science 277, 2002–2004 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Nelissen, I. et al. Gelatinase B/matrix metalloproteinase-9 cleaves interferon-β and is a target for immunotherapy. Brain 126, 1371–1381 (2003).

    PubMed  Article  Google Scholar 

  75. 75

    Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    Suzuki, M., Raab, G., Moses, M. A., Fernandez, C. A. & Klagsbrun, M. Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site. J. Biol. Chem. 272, 31730–31737 (1997).

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Levi, E. et al. Matrix metalloproteinase 2 releases active soluble ectodomain of fibroblast growth factor receptor 1. Proc. Natl Acad. Sci. USA 93, 7069–7074 (1996).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β 1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79

    Kulkarni, A. B. & Karlsson, S. Transforming growth factor-β 1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am. J. Pathol. 143, 3–9 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Maeda, S., Dean, D. D., Gomez, R., Schwartz, Z. & Boyan, B. D. The first stage of transforming growth factor β1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3). Calcif. Tissue Int. 70, 54–65 (2002).

    CAS  PubMed  Article  Google Scholar 

  82. 82

    Karsdal, M. A. et al. Matrix metalloproteinase-dependent activation of latent transforming growth factor-β controls the conversion of osteoblasts into osteocytes by blocking osteoblast apoptosis. J. Biol. Chem. 277, 44061–44067 (2002).

    CAS  PubMed  Article  Google Scholar 

  83. 83

    Fantuzzi, G. et al. Response to local inflammation of IL-1β-converting enzyme-deficient mice. J. Immunol. 158, 1818–1824 (1997).

    CAS  PubMed  Google Scholar 

  84. 84

    Schonbeck, U., Mach, F. & Libby, P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. J. Immunol. 161, 3340–3346 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Ito, A. et al. Degradation of interleukin 1β by matrix metalloproteinases. J. Biol. Chem. 271, 14657–14660 (1996).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Gearing, A. J. H. et al. Processing of tumour necrosis factor-α precursor by metalloproteinases. Nature 370, 555–557 (1994).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88

    Moss, M. L. et al. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 385, 733–736 (1997).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Mohan, M. J. et al. The tumor necrosis factor-α converting enzyme (TACE): a unique metalloproteinase with highly defined substrate selectivity. Biochemistry 41, 9462–9469 (2002).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    English, W. R. et al. Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-α convertase activity but does not activate pro-MMP2. J. Biol. Chem. 275, 14046–14055 (2000).

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Visse, R. & Nagase, H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 92, 827–839 (2003).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Qi, J. H. et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9, 407–415 (2003).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Seo, D. W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171–180 (2003).

    CAS  PubMed  Article  Google Scholar 

  94. 94

    Oh, J. et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107, 789–800 (2001).

    CAS  PubMed  Article  Google Scholar 

  95. 95

    Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96

    Overall, C. M. & Lopez-Otin, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nature Rev. Cancer 2, 657–672 (2002).

    CAS  Article  Google Scholar 

  97. 97

    Mott, J. D. et al. Post-translational proteolytic processing of procollagen C-terminal proteinase enhancer releases a metalloproteinase inhibitor. J. Biol. Chem. 275, 1384–1390 (2000).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Belaaouaj, A. et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Med. 4, 615–618 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

    Liu, Z. et al. The serpin α1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 102, 647–655 (2000). Using an experimental model of blister formation, this paper shows that MMP9 contributes to inflammation-mediated tissue damage by cleaving and inactivating the serpin α1-antiproteinase (a potent inhibitor of neutrophil elastase).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Lochter, A. et al. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J. Cell Biol. 139, 1861–1872 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101

    Sympson, C. J. et al. Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J. Cell Biol. 125, 681–693 (1994).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Haro, H. et al. Matrix metalloproteinase-7-dependent release of tumor necrosis factor-α in a model of herniated disc resorption. J. Clin. Invest. 105, 143–150 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103

    Asahi, M. et al. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    Lelongt, B. et al. Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J. Exp. Med. 193, 793–802 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105

    Larsen, P. H., Wells, J. E., Stallcup, W. B., Opdenakker, G. & Yong, V. W. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135 (2003).

    CAS  PubMed  Article  Google Scholar 

  106. 106

    Churg, A. et al. Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-α release. Am. J. Respir. Crit. Care Med. 167, 1083–1089 (2003).

    PubMed  Article  Google Scholar 

  107. 107

    Hotary, K. B. et al. Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes. J. Exp. Med. 195, 295–308 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108

    Endo, K. et al. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J. Biol. Chem. 278, 40764–40770 (2003).

    CAS  PubMed  Article  Google Scholar 

  109. 109

    Koshikawa, N. et al. Proteolytic processing of laminin-5 by MT1-MMP in tissues and its effects on epithelial cell morphology. FASEB J. 18, 364–366 (2004).

    CAS  PubMed  Article  Google Scholar 

  110. 110

    Caterina, J. J. et al. Enamelysin (matrix metalloproteinase 20)-deficient mice display an amelogenesis imperfecta phenotype. J. Biol. Chem. 277, 49598–49604 (2002).

    CAS  PubMed  Article  Google Scholar 

  111. 111

    Billinghurst, R. C. et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J. Clin. Invest. 99, 1534–1545 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112

    Otterness, I. G. et al. Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody. Matrix Biol. 18, 331–341 (1999).

    CAS  PubMed  Article  Google Scholar 

  113. 113

    Wu, W. et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum. 46, 2087–2094 (2002).

    CAS  PubMed  Article  Google Scholar 

  114. 114

    Hotary, K. B. et al. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114, 33–45 (2003).

    CAS  PubMed  Article  Google Scholar 

  115. 115

    Balbin, M. et al. Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J. Biol. Chem. 276, 10253–10262 (2001).

    CAS  PubMed  Article  Google Scholar 

  116. 116

    Cossins, J., Dudgeon, T. J., Catlin, G., Gearing, A. J. & Clements, J. M. Identification of MMP-18, a putative novel human matrix metalloproteinase. Biochem. Biophys. Res. Commun. 228, 494–498 (1996).

    CAS  PubMed  Article  Google Scholar 

  117. 117

    Stolow, M. A. et al. Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development. Mol. Biol. Cell 7, 1471–1483 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118

    Clark, H. F. et al. The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res. 13, 2265–2270 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119

    Itoh, T. et al. Reduced angiogenesis and tumor progression in gelatinase A-deficient mice. Cancer Res. 58, 1048–1051 (1998).

    CAS  PubMed  Google Scholar 

  120. 120

    Kato, T. et al. Diminished corneal angiogenesis in gelatinase A-deficient mice. FEBS Lett. 508, 187–190 (2001).

    CAS  PubMed  Article  Google Scholar 

  121. 121

    Ohno-Matsui, K. et al. Reduced retinal angiogenesis in MMP-2-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 5370–5375 (2003).

    PubMed  Article  Google Scholar 

  122. 122

    Berglin, L. et al. Reduced choroidal neovascular membrane formation in matrix metalloproteinase-2-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 403–408 (2003).

    PubMed  Article  Google Scholar 

  123. 123

    Wang, M. et al. Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response. Proc. Natl Acad. Sci. USA 96, 6885–6889 (1999).

    CAS  PubMed  Article  Google Scholar 

  124. 124

    Warner, R. L. et al. Role of stromelysin 1 and gelatinase B in experimental acute lung injury. Am. J. Respir. Cell Mol. Biol. 24, 537–544 (2001).

    CAS  PubMed  Article  Google Scholar 

  125. 125

    Silence, J., Lupu, F., Collen, D. & Lijnen, H. R. Persistence of atherosclerotic plaque but reduced aneurysm formation in mice with stromelysin-1 (MMP-3) gene inactivation. Arterioscler. Thromb. Vasc. Biol. 21, 1440–1445 (2001).

    CAS  PubMed  Article  Google Scholar 

  126. 126

    Kure, T. et al. Corneal neovascularization after excimer keratectomy wounds in matrilysin-deficient mice. Invest. Ophthalmol. Vis. Sci. 44, 137–144 (2003).

    PubMed  Article  Google Scholar 

  127. 127

    Dubois, B. et al. Resistance of young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis and necrotizing tail lesions. J. Clin. Invest. 104, 1507–1515 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128

    Dubois, B. et al. Gelatinase B deficiency protects against endotoxin shock. Eur. J. Immunol. 32, 2163–2171 (2002).

    CAS  PubMed  Article  Google Scholar 

  129. 129

    Ratzinger, G. et al. Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin. J. Immunol. 168, 4361–4371 (2002).

    CAS  PubMed  Article  Google Scholar 

  130. 130

    Liu, Z. et al. Gelatinase B-deficient mice are resistant to experimental bullous pemphigoid. J. Exp. Med. 188, 475–482 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131

    Vu, T. H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132

    Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133

    Johnson, C., Sung, H. J., Lessner, S. M., Fini, M. E. & Galis, Z. S. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching. Circ. Res. 94, 262–268 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

    McMillan, S. J. et al. Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation. J. Immunol. 172, 2586–2594 (2004).

    CAS  PubMed  Article  Google Scholar 

  135. 135

    Cataldo, D. D. et al. Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am. J. Pathol. 161, 491–498 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136

    Lanone, S. et al. Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and-12 in IL-13-induced inflammation and remodeling. J. Clin. Invest. 110, 463–474 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137

    Luttun, A. et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 109, 1408–1414 (2004).

    CAS  PubMed  Article  Google Scholar 

  138. 138

    Longo, G. M. et al. Matrix metalloproteinase 2 and 9 work in concert to produce aortic aneurysms. J. Clin. Invest. 110, 625–632 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139

    Pyo, R. et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J. Clin. Invest. 105, 1641–1649 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140

    Asahi, M. et al. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J. Cereb. Blood Flow Metab. 20, 1681–1689 (2000).

    CAS  PubMed  Article  Google Scholar 

  141. 141

    Lambert, V. et al. MMP-2 and MMP-9 synergize in promoting choroidal neovascularization. FASEB J. 17, 2290–2292 (2003).

    CAS  PubMed  Article  Google Scholar 

  142. 142

    Shipley, J. M., Wesselschmidt, R. L., Kobayashi, D. K., Ley, T. J. & Shapiro, S. D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc. Natl Acad. Sci. USA 93, 3942–3946 (1996).

    CAS  PubMed  Article  Google Scholar 

  143. 143

    Wells, J. E. et al. An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice. J. Neurosci. 23, 10107–10115 (2003).

    CAS  PubMed  Article  Google Scholar 

  144. 144

    Warner, R. L. et al. The role of metalloelastase in immune complex-induced acute lung injury. Am. J. Pathol. 158, 2139–2144 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Correspondence to William C. Parks.

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DATABASES

Entrez Gene

ADAM17

CCL7

CXCL1

CXCL8

FAS

FASL

IL-1β

MMPs

syndecan-1

TGF-β1

TNF

Glossary

PRO-DOMAIN

The matrix metalloproteinase (MMP) pro-peptide region (or pro-domain) contains 80 amino acids, typically with a hydrophobic residue at the amino terminus. It also contains the highly conserved sequence PRCXXPD, where X denotes any amino acid. The thiol group of the cysteine residue in this sequence ligates with the zinc ion that is held by the histidine residues in the catalytic domain of the MMP. In this state, the enzyme is stable and inactive and is known as a zymogen.

CATALYTIC-DOMAIN

The typical matrix metalloproteinase catalytic domain contains 160–170 residues, including the binding sites for the structural (calcium and zinc) and catalytic (zinc) metal ions. The 50–54 residues at the carboxyl terminus of the catalytic domain include a highly conserved HEXXHXXGXXH sequence (where X denotes any amino acid), which includes a glutamic acid residue (E) that provides the nucleophile that severs peptide bonds and histidine residues that coordinate the zinc ions.

MET TURN

On the carboxy side of the zinc active site, matrix metalloproteinases have a methionine residue that is always conserved. This residue is part of a 1,4-β-turn that loops the polypeptide chain beneath the catalytic zinc ion and forms a hydrophobic base for the zinc-binding site.

ADAM

A disintegrin and metalloproteinase family of proteases. They contain disintegrin-like and metalloproteinase-like domains and are involved in the regulation of developmental processes, cell–cell interactions and protein processing, including ectodomain shedding.

CLAN

The superfamily of metalloenzymes includes more than 200 members. It has been divided into eight clans based on the similarity of protein folding characteristics and 40 families according to evolutionary relationships. The matrix-metalloproteinase family belongs to clan MB, the members of which have three histidine residues as zinc-binding ligands in the consensus sequence HEXXHXXGXXH (where X denotes any amino acid).

HINGE REGION

A domain that is typically 75 residues and links the catalytic domain to the hemopexin-like domain of most matrix metalloproteinases.

HEMOPEXIN-LIKE DOMAIN

This matrix-metalloproteinase domain comprises 200 residues and contains four repeats that resemble hemopexin and vitronectin. It is not essential for catalytic activity but does modulate substrate specificity and binding to tissue inhibitors of metalloproteinases.

GLYCOSYLPHOSPHAT- IDYLINOSITOL (GPI)-ANCHORING SIGNALS

A glycolipid modification that is usually located at the carboxyl terminus and anchors proteins to the external surface of the plasma membrane.

GELATIN-BINDING DOMAINS

These domains contain three fibronectin-like modules (also known as fibronectin type II modules) and are present in the catalytic domain of both matrix metalloproteinase 2 and -9.

CYSTEINE-SWITCH MECHANISM

The pro-peptide maintains a matrix metalloproteinase (MMP) in an inactive state. When the interaction between the conserved cysteine residue in the pro-domain and the active site zinc ion is disrupted (for example, by proteolytic removal of the pro-peptide or by the action of organomercurials and chaotropic agents on the thiol of the cysteine residue), the active site becomes accessible, and the MMP has been 'activated'. The pro-domain does not need to be removed for a proMMP to acquire activity; only disruption of the zinc–thiol interaction is absolutely required.

TIMPs

Tissue inhibitors of metalloproteinases. A family of four (TIMP1, -2, -3 and -4) endogenous matrix-metalloproteinase (MMP) inhibitors that bind the catalytic site in activated enzymes. TIMP1 and TIMP3 also bind the hemopexin-like domain of the MMP9 and MMP13 zymogens, whereas TIMP2, -3 and -4 can bind this domain in the MMP2 zymogen.

CHEMOKINES

A family of structurally related, small glycoproteins (70–90 amino acids) that have potent leukocyte activation and/or chemotactic activity. They have pivotal roles in innate and acquired immunity. These molecules, of which there are more than 50, are classified into four subfamilies depending on the arrangement of the amino-terminal conserved cysteine residues: CC-, CXC-, C- and CX3C-chemokines (where X denotes any amino acid). In general, CC-chemokines attract monocytes, lymphocytes, basophils and eosinophils, whereas CXC-chemokines are chemotactic for neutrophils.

INNATE IMMUNITY

The term generally refers to innate pathogen-recognition systems, as well as to antimicrobial peptides. Innate immunity comprises immediate responses that are generated without the requirement for memory of, or prior exposure to, the pathogen. It is mostly mediated by receptors that have broad specificity (such as Toll-like receptors): that is, receptors that recognize many related pathogen-associated molecular patterns.

RE-EPITHELIALIZATION

A mechanism of repair that involves epithelial-cell proliferation and migration across a denuded surface to re-establish cell contact and close a wound. During re-epithelialization, cells receive and process cues from a new microenvironment (that is, the exposed wound) and coordinate various responses, including the induction of matrix metalloproteinases and pro-inflammatory mediators, and the activation and expression of integrins.

DEFENSINS

A class of antimicrobial peptides that have activity against Gram-positive and Gram-negative bacteria, fungi and viruses. Defensins are classified into two main categories on the basis of the position of conserved cysteine and hydrophobic residues and the linkages of disulphide bonds: α-defensins are produced by intestinal Paneth cells and neutrophils, and β-defensins are expressed by most epithelial cells. A third category, the θ-defensins, arises from the splicing of two α-defensin-related peptides into a circular molecule; at present, these defensins have been detected only in the neutrophils of rhesus macaques.

NEUTROPHIL TRANSEPITHELIAL MIGRATION

During bacterial infections at mucosal sites, neutrophils migrate from the vasculature through the interstitial compartment and across the epithelial barrier. The activation and migration of neutrophils into lungs also contributes to inflammatory tissue injury and remodelling of tissue architecture

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Parks, W., Wilson, C. & López-Boado, Y. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 4, 617–629 (2004). https://doi.org/10.1038/nri1418

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