1887
No metrics data to plot.
The attempt to load metrics for this article has failed.
The attempt to plot a graph for these metrics has failed.

Metalloproteinases: a Functional Pathway for Myeloid Cells

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
Buy this Microbiology Spectrum Article
Price Non-Member $15.00
  • Authors: Jonathan Chou1, Matilda F. Chan3, Zena Werb4
  • Editor: Siamon Gordon5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Anatomy, University of California, San Francisco, CA 94143; 2: Department of Medicine, University of California, San Francisco, CA 94143; 3: Department of Ophthalmology, University of California, San Francisco, CA 94143; 4: Department of Anatomy, University of California, San Francisco, CA 94143; 5: Oxford University, Oxford, United Kingdom
  • Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.MCHD-0002-2015
  • Received 31 March 2015 Accepted 14 August 2015 Published 22 April 2016
  • Zena Werb, zena.werb@ucsf.edu
image of Metalloproteinases: a Functional Pathway for Myeloid Cells
    Preview this microbiology spectrum article:
    Zoom in
    Zoomout

    Metalloproteinases: a Functional Pathway for Myeloid Cells, Page 1 of 2

    | /docserver/preview/fulltext/microbiolspec/4/2/MCHD-0002-2015-1.gif /docserver/preview/fulltext/microbiolspec/4/2/MCHD-0002-2015-2.gif
  • Abstract:

    Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration, and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis, and cancer. Metalloproteinases also have important nonproteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote antiviral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions.

  • Citation: Chou J, Chan M, Werb Z. 2016. Metalloproteinases: a Functional Pathway for Myeloid Cells. Microbiol Spectrum 4(2):MCHD-0002-2015. doi:10.1128/microbiolspec.MCHD-0002-2015.

Key Concept Ranking

Tumor Necrosis Factor
0.6097461
Mast Cells
0.4825807
Immune Response
0.43498778
Reactive Oxygen Species
0.4311134
0.6097461

References

1. Lazarus GS, Brown RS, Daniels JR, Fullmer HM. 1968. Human granulocyte collagenase. Science 159:1483–1485. [PubMed][CrossRef]
2. Sopata I, Dancewicz AM. 1974. Presence of a gelatin-specific proteinase and its latent form in human leucocytes. Biochim Biophys Acta 370:510–523. [PubMed][CrossRef]
3. Gordon S, Werb Z. 1976. Secretion of macrophage neutral proteinase is enhanced by colchicine. Proc Natl Acad Sci U S A 73:872–876. [PubMed][CrossRef]
4. Werb Z, Bainton DF, Jones PA. 1980. Degradation of connective tissue matrices by macrophages. III. Morphological and biochemical studies on extracellular, pericellular, and intracellular events in matrix proteolysis by macrophages in culture. J Exp Med 152:1537–1553. [PubMed][CrossRef]
5. Werb Z, Banda MJ, Jones PA. 1980. Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. J Exp Med 152:1340–1357. [PubMed][CrossRef]
6. Werb Z, Gordon S. 1975. Elastase secretion by stimulated macrophages. Characterization and regulation. J Exp Med 142:361–377. [PubMed][CrossRef]
7. Werb Z, Gordon S. 1975. Secretion of a specific collagenase by stimulated macrophages. J Exp Med 142:346–360. [PubMed][CrossRef]
8. Lu P, Takai K, Weaver VM, Werb Z. 2011. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3:a005058. doi:10.1101/cshperspect.a005058. [PubMed][CrossRef]
9. Bonnans C, Chou J, Werb Z. 2014. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15:786–801. [PubMed][CrossRef]
10. Van Wart HE, Birkedal-Hansen H. 1990. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 87:5578–5582. [PubMed][CrossRef]
11. Page-McCaw A, Ewald AJ, Werb Z. 2007. Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8:221–233. [PubMed][CrossRef]
12. Marco M, Fortin C, Fulop T. 2013. Membrane-type matrix metalloproteinases: key mediators of leukocyte function. J Leukoc Biol 94:237–246. [PubMed][CrossRef]
13. Kuno K, Kanada N, Nakashima E, Fujiki F, Ichimura F, Matsushima K. 1997. Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene. J Biol Chem 272:556–562. [PubMed][CrossRef]
14. Lisi S, D’Amore M, Sisto M. 2014. ADAM17 at the interface between inflammation and autoimmunity. Immunol Lett 162:159–169. [PubMed][CrossRef]
15. Murphy G. 2008. The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer 8:929–941. [PubMed][CrossRef]
16. Apte SS. 2009. A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms. J Biol Chem 284:31493–31497. [PubMed][CrossRef]
17. Yamamoto K, Murphy G, Troeberg L. 2015. Extracellular regulation of metalloproteinases. Matrix Biol 44–46:255–263. [PubMed][CrossRef]
18. Uekita T, Itoh Y, Yana I, Ohno H, Seiki M. 2001. Cytoplasmic tail-dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity. J Cell Biol 155:1345–1356. [PubMed][CrossRef]
19. Piccard H, Van den Steen PE, Opdenakker G. 2007. Hemopexin domains as multifunctional liganding modules in matrix metalloproteinases and other proteins. J Leukoc Biol 81:870–892. [PubMed][CrossRef]
20. Barmina OY, Walling HW, Fiacco GJ, Freije JM, López-Otín C, Jeffrey JJ, Partridge NC. 1999. Collagenase-3 binds to a specific receptor and requires the low density lipoprotein receptor-related protein for internalization. J Biol Chem 274:30087–30093. [PubMed][CrossRef]
21. Hahn-Dantona E, Ruiz JF, Bornstein P, Strickland DK. 2001. The low density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolism. J Biol Chem 276:15498–15503. [PubMed][CrossRef]
22. Khokha R, Murthy A, Weiss A. 2013. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 13:649–665. [PubMed][CrossRef]
23. Nagase H, Visse R, Murphy G. 2006. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69:562–573. [PubMed][CrossRef]
24. Scilabra SD, Troeberg L, Yamamoto K, Emonard H, Thøgersen I, Enghild JJ, Strickland DK, Nagase H. 2012. Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1. J Biol Chem 288:332–342. [PubMed][CrossRef]
25. Thevenard J, Verzeaux L, Devy J, Etique N, Jeanne A, Schneider C, Hachet C, Ferracci G, David M, Martiny L, Charpentier E, Khrestchatisky M, Rivera S, Dedieu S, Emonard H. 2014. Low-density lipoprotein receptor-related protein-1 mediates endocytic clearance of tissue inhibitor of metalloproteinases-1 and promotes its cytokine-like activities. PLoS One 9:e103839. doi:10.1371/journal.pone.0103839. [CrossRef]
26. Masure S, Proost P, Van Damme J, Opdenakker G. 1991. Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8. Eur J Biochem 198:391–398. [PubMed][CrossRef]
27. Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP. 2007. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci U S A 104:20262–20267. [PubMed][CrossRef]
28. Shi F, Sottile J. 2011. MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin. J Cell Sci 124:4039–4050. [PubMed][CrossRef]
29. Di Girolamo N, Indoh I, Jackson N, Wakefield D, McNeil HP, Yan W, Geczy C, Arm JP, Tedla N. 2006. Human mast cell-derived gelatinase B (matrix metalloproteinase-9) is regulated by inflammatory cytokines: role in cell migration. J Immunol 177:2638–2650. [PubMed][CrossRef]
30. Bradley LM, Douglass MF, Chatterjee D, Akira S, Baaten BJ. 2012. Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS Pathog 8:e1002641. doi:10.1371/journal.ppat.1002641. [CrossRef]
31. Awla D, Abdulla A, Syk I, Jeppsson B, Regner S, Thorlacius H. 2012. Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis. J Leukoc Biol 91:711–719. [PubMed][CrossRef]
32. Dean RA, Cox JH, Bellac CL, Doucet A, Starr AE, Overall CM. 2008. Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx. Blood 112:3455–3464. [PubMed][CrossRef]
33. Pruessmeyer J, Hess FM, Alert H, Groth E, Pasqualon T, Schwarz N, Nyamoya S, Kollert J, van der Vorst E, Donners M, Martin C, Uhlig S, Saftig P, Dreymueller D, Ludwig A. 2014. Leukocytes require ADAM10 but not ADAM17 for their migration and inflammatory recruitment into the alveolar space. Blood 123:4077–4088. [PubMed][CrossRef]
34. Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP. 1997. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385:729–733. [PubMed][CrossRef]
35. Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD. 1997. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α. Nature 385:733–736. [PubMed][CrossRef]
36. Horiuchi K, Kimura T, Miyamoto T, Takaishi H, Okada Y, Toyama Y, Blobel CP. 2007. Cutting edge: TNF-α-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock. J Immunol 179:2686–2689. [PubMed][CrossRef]
37. Scheller J, Chalaris A, Garbers C, Rose-John S. 2011. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 32:380–387. [PubMed][CrossRef]
38. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD. 2006. Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest 116:753–759. [PubMed][CrossRef]
39. Rovida E, Paccagnini A, Del Rosso M, Peschon J, Dello Sbarba P. 2001. TNF-α-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation. J Immunol 166:1583–1589. [PubMed][CrossRef]
40. Knolle MD, Nakajima T, Hergrueter A, Gupta K, Polverino F, Craig VJ, Fyfe SE, Zahid M, Permaul P, Cernadas M, Montano G, Tesfaigzi Y, Sholl L, Kobzik L, Israel E, Owen CA. 2013. Adam8 limits the development of allergic airway inflammation in mice. J Immunol 190:6434–6449. [PubMed][CrossRef]
41. Chan MF, Li J, Bertrand A, Casbon AJ, Lin JH, Maltseva I, Werb Z. 2013. Protective effects of matrix metalloproteinase-12 following corneal injury. J Cell Sci 126:3948–3960. [PubMed][CrossRef]
42. Houghton AM, Hartzell WO, Robbins CS, Gomis-Ruth FX, Shapiro SD. 2009. Macrophage elastase kills bacteria within murine macrophages. Nature 460:637–641. [PubMed][CrossRef]
43. Marchant DJ, Bellac CL, Moraes TJ, Wadsworth SJ, Dufour A, Butler GS, Bilawchuk LM, Hendry RG, Robertson AG, Cheung CT, Ng J, Ang L, Luo Z, Heilbron K, Norris MJ, Duan W, Bucyk T, Karpov A, Devel L, Georgiadis D, Hegele RG, Luo H, Granville DJ, Dive V, McManus BM, Overall CM. 2014. A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med 20:493–502. [PubMed][CrossRef]
44. Shimizu-Hirota R, Xiong W, Baxter BT, Kunkel SL, Maillard I, Chen XW, Sabeh F, Liu R, Li XY, Weiss SJ. 2012. MT1-MMP regulates the PI3Kδ·Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev 26:395–413. [PubMed][CrossRef]
45. Gonzalo P, Guadamillas MC, Hernández-Riquer MV, Pollán A, Grande-García A, Bartolomé RA, Vasanji A, Ambrogio C, Chiarle R, Teixidó J, Risteli J, Apte SS, del Pozo MA, Arroyo AG. 2010. MT1-MMP is required for myeloid cell fusion via regulation of Rac1 signaling. Dev Cell 18:77–89. [PubMed][CrossRef]
46. Kessenbrock K, Plaks V, Werb Z. 2010. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141:52–67. [PubMed][CrossRef]
47. Lohela M, Casbon AJ, Olow A, Bonham L, Branstetter D, Weng N, Smith J, Werb Z. 2014. Intravital imaging reveals distinct responses of depleting dynamic tumor-associated macrophage and dendritic cell subpopulations. Proc Natl Acad Sci U S A 111:E5086–E5095. [PubMed][CrossRef]
48. Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, Passegué E, Werb Z. 2015. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci U S A 112:E566–E575. [PubMed][CrossRef]
49. Coussens LM, Tinkle CL, Hanahan D, Werb Z. 2000. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103:481–490. [PubMed][CrossRef]
50. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, Tanzawa K, Thorpe P, Itohara S, Werb Z, Hanahan D. 2000. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2:737–744. [PubMed][CrossRef]
51. Nakasone ES, Askautrud HA, Kees T, Park JH, Plaks V, Ewald AJ, Fein M, Rasch MG, Tan YX, Qiu J, Park J, Sinha P, Bissell MJ, Frengen E, Werb Z, Egeblad M. 2012. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21:488–503. [PubMed][CrossRef]
52. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D. 2005. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827. [PubMed][CrossRef]
53. Huang Y, Song N, Ding Y, Yuan S, Li X, Cai H, Shi H, Luo Y. 2009. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res 69:7529–7537. [PubMed][CrossRef]
54. Kessenbrock K, Dijkgraaf GJ, Lawson DA, Littlepage LE, Shahi P, Pieper U, Werb Z. 2013. A role for matrix metalloproteinases in regulating mammary stem cell function via the Wnt signaling pathway. Cell Stem Cell 13:300–313. [PubMed][CrossRef]
55. Correia AL, Mori H, Chen EI, Schmitt FC, Bissell MJ. 2013. The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90β. Genes Dev 27:805–817. [PubMed][CrossRef]
56. Balbin M, Fueyo A, Tester AM, Pendás AM, Pitiot AS, Astudillo A, Overall CM, Shapiro SD, López-Otín C. 2003. Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat Genet 35:252–257. [PubMed][CrossRef]
57. Palavalli LH, Prickett TD, Wunderlich JR, Wei X, Burrell AS, Porter-Gill P, Davis S, Wang C, Cronin JC, Agrawal NS, Lin JC, Westbroek W, Hoogstraten-Miller S, Molinolo AA, Fetsch P, Filie AC, O’Connell MP, Banister CE, Howard JD, Buckhaults P, Weeraratna AT, Brody LC, Rosenberg SA, Samuels Y. 2009. Analysis of the matrix metalloproteinase family reveals that MMP8 is often mutated in melanoma. Nat Genet 41:518–520. [PubMed][CrossRef]
58. Houghton AM, Grisolano JL, Baumann ML, Kobayashi DK, Hautamaki RD, Nehring LC, Cornelius LA, Shapiro SD. 2006. Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases. Cancer Res 66:6149–6155. [PubMed][CrossRef]
59. Yoda M, Kimura T, Tohmonda T, Uchikawa S, Koba T, Takito J, Morioka H, Matsumoto M, Link DC, Chiba K, Okada Y, Toyama Y, Horiuchi K. 2011. Dual functions of cell-autonomous and non-cell-autonomous ADAM10 activity in granulopoiesis. Blood 118:6939–6942. [PubMed][CrossRef]
60. Coussens LM, Fingleton B, Matrisian LM. 2002. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295:2387–2392. [PubMed][CrossRef]
61. Remacle AG, Golubkov VS, Shiryaev SA, Dahl R, Stebbins JL, Chernov AV, Cheltsov AV, Pellecchia M, Strongin AY. 2012. Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth. Cancer Res 72:2339–2349. [PubMed][CrossRef]
62. Tam EM, Morrison CJ, Wu YI, Stack MS, Overall CM. 2004. Membrane protease proteomics: isotope-coded affinity tag MS identification of undescribed MT1-matrix metalloproteinase substrates. Proc Natl Acad Sci U S A 101:6917–6922. [PubMed][CrossRef]
63. Wolf K, Wu YI, Liu Y, Geiger J, Tam E, Overall C, Stack MS, Friedl P. 2007. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol 9:893–904. [PubMed][CrossRef]
64. Zeisberg M, Khurana M, Rao VH, Cosgrove D, Rougier JP, Werner MC, Shield CF III, Werb Z, Kalluri R. 2006. Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med 3:e100. doi:10.1371/journal.pmed.0030100. [CrossRef]
65. Bellac CL, Dufour A, Krisinger MJ, Loonchanta A, Starr AE, Auf dem Keller U, Lange PF, Goebeler V, Kappelhoff R, Butler GS, Burtnick LD, Conway EM, Roberts CR, Overall CM. 2014. Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis. Cell Rep 9:618–632. [PubMed][CrossRef]
66. Gong Y, Hart E, Shchurin A, Hoover-Plow J. 2008. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest 118:3012–3024. [PubMed][CrossRef]
67. Liu Z, Zhou X, Shapiro SD, Shipley JM, Twining SS, Diaz LA, Senior RM, Werb Z. 2000. The serpin α1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell 102:647–655. [PubMed][CrossRef]
68. Shimanovich I, Mihai S, Oostingh GJ, Ilenchuk TT, Brocker EB, Opdenakker G, Zillikens D, Sitaru C. 2004. Granulocyte-derived elastase and gelatinase B are required for dermal-epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid. J Pathol 204:519–527. [PubMed][CrossRef]
69. Liu Z, Li N, Diaz LA, Shipley M, Senior RM, Werb Z. 2005. Synergy between a plasminogen cascade and MMP-9 in autoimmune disease. J Clin Invest 115:879–887. [PubMed][CrossRef]
70. Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD. 1998. Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:6845–6852. [PubMed]
71. Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H, Shipley JM, Senior RM, Shibuya M. 2002. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2:289–300. [PubMed][CrossRef]
microbiolspec.MCHD-0002-2015.citations
cm/4/2
content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0002-2015
Loading

Citations loading...

Loading

Article metrics loading...

/content/journal/microbiolspec/10.1128/microbiolspec.MCHD-0002-2015
2016-04-22
2017-09-21

Abstract:

Myeloid cells have diverse roles in regulating immunity, inflammation, and extracellular matrix turnover. To accomplish these tasks, myeloid cells carry an arsenal of metalloproteinases, which include the matrix metalloproteinases and the adamalysins. These enzymes have diverse substrate repertoires, and are thus involved in mediating proteolytic cascades, cell migration, and cell signaling. Dysregulation of metalloproteinases contributes to pathogenic processes, including inflammation, fibrosis, and cancer. Metalloproteinases also have important nonproteolytic functions in controlling cytoskeletal dynamics during macrophage fusion and enhancing transcription to promote antiviral immunity. This review highlights the diverse contributions of metalloproteinases to myeloid cell functions.

Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

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.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.MCHD-0002-2015
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2
FIGURE 2

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 () 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.

Source: microbiolspec April 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.MCHD-0002-2015
Permissions and Reprints Request Permissions
Download as Powerpoint

Supplemental Material

No supplementary material available for this content.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error