Synergy between a plasminogen cascade and MMP-9 in autoimmune disease

Li, Zhi; Li, Ning; Díaz, Luis A.; Shipley, J. Michael; Senior, Robert M.; Werb, Zena

doi:10.1172/jci23977

Cited by 97 publications

(63 citation statements)

References 69 publications

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“…Contrary to previously published data regarding positivity of MMP9 and uPAR in human ABDs and respective animal models, our studies of in situ biopsies from active clinical lesions demonstrate significant differences [11][12][13][14][15]. Specifically, uPAR was positive only in one part of a lesional blister from one case of BP, where the blister demonstrated blood deposits.…”

Section: Discussioncontrasting

confidence: 99%

“…We applied the chromogen 3,3-diaminobenzidine, and counterstained with hematoxylin. The samples were run in a Dako Autostainer Universal Staining System, as previously described (13)(14)(15) . We also utilized control tissue from 4 non-El Bagre EPF patient autopsies (from the El Bagre EPF endemic area), to rule out false positive and false negative results due to spontaneous autolysis.…”

Section: Immunohistochemistry Stainingmentioning

confidence: 99%

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Tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 9, αlpha-1 antitrypsin, metallothionein and urokinase type plasminogen activator receptor in skin biopsies from patients affected by autoimmune blistering diseases

Velez¹,

Naranjo²,

Ávila³

et al. 2013

Our Dermatol Online

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Introduction: Proteinases and proteinase inhibitors have been described to play a role in autoimmune skin blistering diseases. We studied skin lesional biopsies from patients affected by several autoimmune skin blistering diseases for proteinases and proteinase inhibitors. Methods: We utilized immunohistochemistry to evaluate biopsies for α-1-antitrypsin, human matrix metalloproteinase 9 (MMP9), human tissue inhibitor of metalloproteinases 1 (TIMP-1), metallothionein and urokinase type plasminogen activator receptor (uPAR). We tested 30 patients affected by endemic pemphigus, 30 controls from the endemic area, and 15 normal controls. We also tested 30 biopsies from patients with bullous pemphigoid (BP), 20 with pemphigus vulgaris (PV), 8 with pemphigus foliaceus, and 14 with dermatitis herpetiformis (DH). Results: Contrary to findings in the current literature, most autoimmune skin blistering disease biopsies were negative for uPAR and MMP9. Only some chronic patients with El Bagre-EPF were positive to MMP9 in the dermis, in proximity to telocytes. TIMP-1 and metallothionein were positive in half of the biopsies from BP patients at the basement membrane of the skin, within several skin appendices, in areas of dermal blood vessel inflammation and within dermal mesenchymal-epithelial cell junctions.Key words: endemic pemphigus foliaceus; autoimmune blistering skin diseases; matrix metalloproteinase 9; tissue inhibitor of metalloproteinases 1; urokinase type plasminogen activator receptor; α-1-antitrypsin IntroductionMultiple theories have been proposed regarding the pathophysiology of cutaneous autoimmune blistering skin diseases (ABDs). Some involve plasminogen activation, desmoglein compensation, acetylcholine receptor antibodies, and intracellular signal control of autoantibodies [1]. Moreover, human autoantibodies and the presence of complement are primary factors in producing the blisters of human autoimmune skin blistering diseases and are thought to exert their pathogenic effect via proteases [2,3]. Few studies have tested for proteases and protease inhibitors in lesional skin from patients affected by ABDs [4,5]. We decided to investigate enzymes that could be modulated by ions that have been postulated as triggers for ABDs. We also aimed to investigate enzymes that are related to xenobiotics, based on our previous findings of metals and metalloids in skin biopsies of patients with a new variant of endemic pemphigus foliaceus in El Bagre, Colombia (El-Bagre-EPF) that are exposed to significant mercury pollution [5]. Thus, we utilized immunohistochemistry (IHC) to test for anti-human-α-1-antitrypsin, anti-human matrix metalloproteinase 9 (MMP9), anti-human tissue inhibitor of metalloproteinases 1 (TIMP1), urokinase type plasminogen activator receptor (uPAR) and for metallothionein in patients affected by autoimmune skin blistering diseases.

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Section: Discussioncontrasting

confidence: 99%

Section: Immunohistochemistry Stainingmentioning

confidence: 99%

Tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 9, αlpha-1 antitrypsin, metallothionein and urokinase type plasminogen activator receptor in skin biopsies from patients affected by autoimmune blistering diseases

Velez¹,

Naranjo²,

Ávila³

et al. 2013

Our Dermatol Online

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“…For example, MMP9 contributes to inflammation in mouse models of stroke, heart attack, Alzheimer's disease, some aspects of asthma and other lung inflammatory conditions, aortic aneurysms and autoimmune encephalomyelitis 9,[106][107][108][109][110] ; however, it functions as an anti-inflammatory agent in models of inflammatory skin and kidney diseases 89,111,112 . Current data indicate that MMP12 contributes to emphysema 113,114 , whereas MMP3 and MMP9 contribute to skin inflammatory conditions 89,115 . By contrast, MMP8 protects against skin inflammatory responses 104 and MMP2 protects against inflammation of the brain and spinal cord 116 .…”

Section: Mmps In Human Inflammatory Disease Modelsmentioning

confidence: 93%

Matrix metalloproteinases and the regulation of tissue remodelling

Page-McCaw

Ewald

Werb

2007

Nat Rev Mol Cell Biol

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2,589

2,180

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Matrix metalloproteinases (MMPs) were discovered because of their role in amphibian metamorphosis, yet they have attracted more attention because of their roles in disease. Despite intensive scrutiny in vitro, in cell culture and in animal models, the normal physiological roles of these extracellular proteases have been elusive. Recent studies in mice and flies point to essential roles of MMPs as mediators of change and physical adaptation in tissues, whether developmentally regulated, environmentally induced or disease associated.The founding member of the matrix metalloproteinase (MMP) family, collagenase, was identified in 1962 by Gross and Lapiere, who found that tadpole tails during metamorphosis contained an enzyme that could degrade fibrillar collagen 1,2 . Subsequently, an interstitial collagenase, collagenase-1 or MMP1, was found in diseased skin and synovium 3 . In vitro, MMP1 initiates degradation of native fibrillar collagens, crucial components of vertebrate extracellular matrix (ECM), by cleaving the peptide bond between Gly775-Ile776 or Gly775-Lys776 in native type I, II or III collagen molecules 3,4 . Further research led to the discovery of a family of structurally related proteinases (23 in human, 24 in mice), now referred to as the MMP family.Interest in MMPs increased in the late 1960s and early 1970s following observations that MMPs are upregulated in diverse human diseases including rheumatoid arthritis and cancer. Importantly, high levels of MMPs often correlated with poor prognosis in human patients (reviewed in REF. 5 ). However, recent clinical data indicate that the relationship between § These authors contributed equally to this paper. Competing interests statementThe authors declare no competing financial interests. DATABASESThe following terms in this article are linked online to: Entrez Genome: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene DmMmp1 | DmMmp2 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMMPs and disease is not simple; for example, increased MMP activity can enhance tumour progression or can inhibit it (reviewed in REF. 6 ). This complex relationship between MMP expression and cancer has increased the basic and clinical interest in understanding MMP function in vivo, but it has also focused attention on MMPs and pathology, and relatively less attention has been focused on the normal roles of these enzymes. MMP proteolysisMMPs are members of the metzincin group of proteases, which are named after the zinc ion and the conserved Met residue at the active site 11,12 . Recent work has generated a unified peptidase nomenclature 13 Functions of MMP proteolysisHistorically, MMPs were thought to function mainly as enzymes that degrade structural components of the ECM. However, MMP proteolysis can create space for cells to migrate, can produce specific substrate-cleavage fragments with independent biological activity, can MMPs in bone modelling and remodellingBone is an important site of ongoing tissue remodelling during development...

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“…Of note, chemoattractants for precursors of endothelial cell CXCL1, -2, and -3 mRNA levels were drastically induced (.25-fold) at a transcriptional level (Supplemental Table IC), indicating possible involvement of the OSCAR pathway in the regulation of neoangiogenesis. OSCARcollagen signaling upregulated genes encoding components of TLR, TREM-1, and uPA/MMP-9 pathways highly relevant for pathogenesis of RA and other autoimmune diseases (22). Of interest is also the downregulation of the Wnt/fzd pathway that programs DCs to induce tolerogenic responses (23).…”

Section: Signaling By Oscar-collagen Regulates Gene Expression In Dcsmentioning

confidence: 99%

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

Schultz

Nitze

Zeuthen

et al. 2015

The Journal of Immunology

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Osteoclast-associated receptor (OSCAR) is widely expressed on human myeloid cells. Collagen types (Col)I, II, and III have been described as OSCAR ligands, and ColII peptides can induce costimulatory signaling in receptor activator for NF-κB–dependent osteoclastogenesis. In this study, we isolated collagen as an OSCAR-interacting protein from the membranes of murine osteoblasts. We have investigated a functional outcome of the OSCAR–collagen interaction in human monocyte-derived dendritic cells (DCs). OSCAR engagement by ColI/II-induced activation/maturation of DCs is characterized by upregulation of cell surface markers and secretion of cytokines. These collagen-matured DCs (Col-DCs) were efficient drivers of allogeneic and autologous naive T cell proliferation. The T cells expanded by Col-DCs secreted cytokines with no clear T cell polarization pattern. Global RNA profiling revealed that multiple proinflammatory mediators, including cytokines and cytokine receptors, components of the stable immune synapse (namely CD40, CD86, CD80, and ICAM-1), as well as components of TNF and TLR signaling, are transcriptional targets of OSCAR in DCs. Our findings indicate the existence of a novel pathway by which extracellular matrix proteins locally drive maturation of DCs during inflammatory conditions, for example, within synovial tissue of rheumatoid arthritis patients, where collagens become exposed during tissue remodeling and are thus accessible for interaction with infiltrating precursors of DCs.

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Synergy between a plasminogen cascade and MMP-9 in autoimmune disease

Cited by 97 publications

References 69 publications

Tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 9, αlpha-1 antitrypsin, metallothionein and urokinase type plasminogen activator receptor in skin biopsies from patients affected by autoimmune blistering diseases

Tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 9, αlpha-1 antitrypsin, metallothionein and urokinase type plasminogen activator receptor in skin biopsies from patients affected by autoimmune blistering diseases

Matrix metalloproteinases and the regulation of tissue remodelling

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

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