Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure

Gjelstrup, Louise Carstensen; Boesen, Thomas; Kragstrup, Tue Wenzel; Jørgensen, A.; Klein, Nigel; Thiel, Steffen; Deleuran, Bent; Vorup-Jensen, Thomas

doi:10.4049/jimmunol.1000952

Cited by 42 publications

(64 citation statements)

References 75 publications

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“…We show that peritoneal levels of soluble integrin ␤2 are elevated both at the time of initial exiting of resident macrophages and during the slow resolution phase. As shown by studies of synovial fluids (12), the release of soluble integrin ␤2 may buffer leukocyte adhesion thus further limiting leukocyte influx and/or activation. In addition, soluble complexes may retain signaling capabilities.…”

Section: Discussionmentioning

confidence: 99%

“…In human blister fluid, truncated ectodomains of ␣L␤2 (LFA-1) were detected, and neutrophils and monocytes showed a loss of cell surface ␣L␤2 (10). More recently, shedding of integrin ␤2 complexed with different ␣ subunits was shown to be a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis (12). These authors further demonstrated the ability of soluble integrin ␤2 to inhibit monocytic cell adhesion to ICAM-1.…”

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confidence: 91%

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Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

Gomez

Tang

Wilson

et al. 2012

Journal of Biological Chemistry

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Background: Efflux of macrophages limits inflammation. Results: Macrophage integrin ␣M␤2 is cleaved during exiting from inflammatory sites, released ␣M␤2 retains ligand binding capabilities, and inhibition of its metalloproteinase-mediated cleavage impairs macrophage efflux. Conclusion: Metalloproteinase-mediated proteolysis of integrin ␤2 promotes macrophage efflux from inflammatory sites. Significance: Regulated proteolysis of integrin ␤2 during inflammation demonstrates the potential of this mechanism to contribute to resolution of inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

Gomez

Tang

Wilson

et al. 2012

Journal of Biological Chemistry

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“…Hybridoma cells producing monoclonal antibody KIM127, reacting with an epitope of human CD18 (43), were purchased from the American Type Culture Collection (Manassas, VA, USA), and the antibody was purified from culture supernatant as previously described (44). IgG1 from murine myeloma was used as an unspecific control antibody.…”

Section: Methodsmentioning

confidence: 99%

Sialic Acid Residues Are Essential for Cell Lysis Mediated by Leukotoxin from Aggregatibacter actinomycetemcomitans

et al. 2014

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c Leukotoxin (LtxA) from Aggregatibacter actinomycetemcomitans is known to target and lyse ␤ 2 -integrin-expressing cells such as polymorphonuclear leukocytes and macrophages. LtxA is an important virulence factor that facilitates chronic inflammation and is strongly associated with a fast-progressing form of periodontitis caused by the JP2 clone of the bacterium. Here, we show that sialic acid residues are important for LtxA-induced cell lysis, regardless of whether the cell express ␤ 2 -integrin or not. Clearly, removal of sialic acid groups significantly reduces a ␤ 2 -integrin-specific LtxA-induced lysis. Moreover, sialic acid presented on alternative proteins, such as, for instance, on erythrocytes that do not express ␤ 2 -integrin, also makes the cells more sensitive to LtxA. The data also illustrate the importance of the negative charge in order for the sialic acid to associate LtxA with the membrane. Removal of sialic acid is in itself sufficient to significantly reduce the negative charge on the erythrocytes. Moreover, we found that on human erythrocytes there is a positive association between the sensitivity to LtxA and the amount of negative charge caused by sialic acid. Interestingly, these features are not shared by all RTX toxins, since ␣-hemolysin from Escherichia coli induced cell lysis of both ␤ 2 -integrin-expressing and nonexpressing cells and this lysis is independent of the presence of sialic acid residues. In conclusion, LtxA not only is cytotoxic to ␤ 2 -integrin-expressing cells but can potentially initiate cell lysis in all cells that present a sufficient density of sialic acid groups on their plasma membrane.

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“…tissues, but also the shed molecules appear to act as dominantnegative inhibitors of CD11 or CD18 function on leukocytes (Gjelstrup et al, 2010).…”

Section: Mmp9 Cleaves 4 Integrinmentioning

confidence: 99%

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice

Pal‐Ghosh

Blanco

Tadvalkar

et al. 2011

Journal of Cell Science

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Integrin α6β4 is an integral membrane protein within hemidesmosomes and it mediates adhesion of epithelial cells to their underlying basement membrane. During wound healing, disassembly of hemidesmosomes must occur for sheet movement-mediated cell migration. The mechanisms of disassembly and reassembly of hemidesmosomes are not fully understood. The current study was initiated to understand the underlying cause of recurrent corneal erosions in the mouse. Here, we show that in vivo: (1) MMP9 levels are elevated and β4 integrin is partially cleaved in epithelial cell extracts derived from debridement wounded corneas; (2) the β4 ectodomain is missing from sites where erosions develop; and (3) β4 cleavage can be reduced by inhibiting MMP activity. Although β4, α3 and β1 integrins were all cleaved by several MMPs, only MMP9 was elevated in cell extracts derived from corneas with erosions. Coimmunoprecipitation studies showed that β4 integrin associates with MMP9, and protein clustering during immunoprecipitation induced proteolytic cleavage of the β4 integrin extracellular domain, generating a 100 kDa β4 integrin cytoplasmic domain fragment. Confocal imaging with three-dimensional reconstruction showed that MMP9 localizes at erosion sites in vivo where the ectodomain of β4 integrin is reduced or absent. MMP activation experiments using cultured corneal and epidermal keratinocytes showed reduced levels of α6β4 and β1 integrins within 20 minutes of phorbol ester treatment. This report is the first to show that β4 integrin associates with MMP9 and that its ectodomain is a target for cleavage by MMP9 in vivo under pathological conditions.

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Shedding of Large Functionally Active CD11/CD18 Integrin Complexes from Leukocyte Membranes during Synovial Inflammation Distinguishes Three Types of Arthritis through Differential Epitope Exposure

Cited by 42 publications

References 75 publications

Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

Metalloproteinase-mediated Shedding of Integrin β2 Promotes Macrophage Efflux from Inflammatory Sites

Sialic Acid Residues Are Essential for Cell Lysis Mediated by Leukotoxin from Aggregatibacter actinomycetemcomitans

MMP9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in mice

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