Transmembrane chemokines: Versatile ‘special agents’ in vascular inflammation

Ludwig, Andreas; Weber, Christian

doi:10.1160/th07-01-0035

Cited by 152 publications

(46 citation statements)

References 126 publications

(98 reference statements)

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“…As seen in Figure 4A, the majority of the compounds included in the array did not differ between serum from WT vs. multiple KO mice. However, the filter array analysis indicated that the levels of CXCL16, a chemokine with known ability to attract T cell populations and NKT cells [32], was reduced in serum of multiple KO animals. Similarly, the filter array approach indicated diminished levels of CXCL16 in lung tissue of multiple KO vs. WT animals (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

“…CXCL16 is unique (together with CXCL1) among chemokines by being expressed as a transmembrane protein [32]. Previous studies have shown that CXCL16 can be shed from the cell surface to generate a soluble chemokine, and it has been shown that this is mediated by classical sheddases such as a disintegrin and metalloproteinase 10 (ADAM10) or ADAM17 [32–34].…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have shown that CXCL16 can be shed from the cell surface to generate a soluble chemokine, and it has been shown that this is mediated by classical sheddases such as a disintegrin and metalloproteinase 10 (ADAM10) or ADAM17 [32–34]. To evaluate the possibility that the differential levels of CXCL16 in WT vs. multiple KO animals is attributed to effects on the expression of sheddases, we compared the expression of the ADAM10 and ADAM17 genes in lungs of WT vs. multiple KO animals.…”

Section: Resultsmentioning

confidence: 99%

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The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

et al. 2017

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Mast cell secretory granules are densely packed with various bioactive mediators including proteases of chymase, tryptase and CPA3 type. Previous studies have indicated that mast cells can affect the outcome of melanoma but the contribution of the mast cell granule proteases to such effects has not been clear. Here we addressed this issue by assessing mice lacking either the chymase Mcpt4, the tryptase Mcpt6 or carboxypeptidase A3 (Cpa3), as well as mice simultaneously lacking all three proteases, in a model of melanoma dissemination from blood to the lung. Although mice with individual deficiency in the respective proteases did not differ significantly from wildtype mice in the extent of melanoma colonization, mice with multiple protease deficiency (Mcpt4/Mcpt6/Cpa3-deficient) exhibited a higher extent of melanoma colonization in lungs as compared to wildtype animals. This was supported by higher expression of melanoma-specific genes in lungs of Mcpt4/Mcpt6/CPA3-deficient vs. wildtype mice. Cytokine profiling showed that the levels of CXCL16, a chemokine with effects on T cell populations and NKT cells, were significantly lower in lungs of Mcpt4/Mcpt6/Cpa3-deficient animals vs. controls, suggesting that multiple mast cell protease deficiency might affect T cell or NKT cell populations. In line with this, we found that the Mcpt4/Mcpt6/Cpa3-deficiency was associated with a reduction in cells expressing CD1d, a MHC class 1-like molecule that is crucial for presenting antigen to invariant NKT (iNKT) cells. Together, these findings indicate a protective role of mast cell-specific proteases in melanoma dissemination, and suggest that this effect involves a CXCL16/CD1d/NKT cell axis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

et al. 2017

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“…Furthermore, the intact membrane-associated form usually functions as an adhesion molecule and scavenger receptor, and can be converted into a soluble form by “a disintegrin and metalloprotease” (ADAM)-10 and ADAM-17 (143–145). The soluble forms act as chemoattractants for different types of immune cells, such as activated T cells (146). Increased concentrations of the soluble form usually reflect inflammation (124, 147, 148).…”

Section: Chemokinesmentioning

confidence: 99%

Regulation of Chemokine Activity – A Focus on the Role of Dipeptidyl Peptidase IV/CD26

et al. 2016

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Chemokines are small, chemotactic proteins that play a crucial role in leukocyte migration and are, therefore, essential for proper functioning of the immune system. Chemokines exert their chemotactic effect by activation of chemokine receptors, which are G protein-coupled receptors (GPCRs), and interaction with glycosaminoglycans (GAGs). Furthermore, the exact chemokine function is modulated at the level of posttranslational modifications. Among the different types of posttranslational modifications that were found to occur in vitro and in vivo, i.e., proteolysis, citrullination, glycosylation, and nitration, NH2-terminal proteolysis of chemokines has been described most intensively. Since the NH2-terminal chemokine domain mediates receptor interaction, NH2-terminal modification by limited proteolysis or amino acid side chain modification can drastically affect their biological activity. An enzyme that has been shown to provoke NH2-terminal proteolysis of various chemokines is dipeptidyl peptidase IV or CD26. This multifunctional protein is a serine protease that preferably cleaves dipeptides from the NH2-terminal region of peptides and proteins with a proline or alanine residue in the penultimate position. Various chemokines possess such a proline or alanine residue, and CD26-truncated forms of these chemokines have been identified in cell culture supernatant as well as in body fluids. The effects of CD26-mediated proteolysis in the context of chemokines turned out to be highly complex. Depending on the chemokine ligand, loss of these two NH2-terminal amino acids can result in either an increased or a decreased biological activity, enhanced receptor specificity, inactivation of the chemokine ligand, or generation of receptor antagonists. Since chemokines direct leukocyte migration in homeostatic as well as pathophysiologic conditions, CD26-mediated proteolytic processing of these chemotactic proteins may have significant consequences for appropriate functioning of the immune system. After introducing the chemokine family together with the GPCRs and GAGs, as main interaction partners of chemokines, and discussing the different forms of posttranslational modifications, this review will focus on the intriguing relationship of chemokines with the serine protease CD26.

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“…Reduced or enhanced receptor affinity/specificity and chemokine activity have been reported, depending on the chemokine and on the type of PTM (4,5). Most PTMs on inflammatory chemokine ligands depend on proteolytic cleavage, with highly specific proteases mainly affecting the NH 2 -terminal region of the protein (2,(5)(6)(7). Many metalloproteases, such as aminopeptidase N/CD13 and various matrix metalloproteases, and a number of serine proteases, including thrombin, plasmin, cathepsin G, and the dipeptidylpeptidase CD26, were reported to cleave specific chemokines in the NH 2 -terminal region.…”

mentioning

confidence: 99%

Citrullination and Proteolytic Processing of Chemokines by Porphyromonas gingivalis

et al. 2014

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eThe outgrowth of Porphyromonas gingivalis within the inflammatory subgingival plaque is associated with periodontitis characterized by periodontal tissue destruction, loss of alveolar bone, periodontal pocket formation, and eventually, tooth loss. Potential virulence factors of P. gingivalis are peptidylarginine deiminase (PPAD), an enzyme modifying free or peptide-bound arginine to citrulline, and the bacterial proteases referred to as gingipains (Rgp and Kgp). Chemokines attract leukocytes during inflammation. However, posttranslational modification (PTM) of chemokines by proteases or human peptidylarginine deiminases may alter their biological activities. Since chemokine processing may be important in microbial defense mechanisms, we investigated whether PTM of chemokines by P. gingivalis enzymes occurs. Upon incubation of interleukin-8 (IL-8; CXCL8) with PPAD, only minor enzymatic citrullination was detected. In contrast, Rgp rapidly cleaved CXCL8 in vitro. Subsequently, different P. gingivalis strains were incubated with the chemokine CXCL8 or CXCL10 and their PTMs were investigated. No significant CXCL8 citrullination was detected for the tested strains. Interestingly, although considerable differences in the efficiency of CXCL8 degradation were observed with full cultures of various strains, similar rates of chemokine proteolysis were exerted by cell-free culture supernatants. Sequencing of CXCL8 incubated with supernatant or bacteria showed that CXCL8 is processed into its more potent forms consisting of amino acids 6 to 77 and amino acids 9 to 77 (the 6-77 and 9-77 forms, respectively). In contrast, CXCL10 was entirely and rapidly degraded by P. gingivalis, with no transient chemokine forms being observed. In conclusion, this study demonstrates PTM of CXCL8 and CXCL10 by gingipains of P. gingivalis and that strain differences may particularly affect the activity of these bacterial membrane-associated proteases.

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Transmembrane chemokines: Versatile ‘special agents’ in vascular inflammation

Cited by 152 publications

References 126 publications

The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

The combined action of mast cell chymase, tryptase and carboxypeptidase A3 protects against melanoma colonization of the lung

Regulation of Chemokine Activity – A Focus on the Role of Dipeptidyl Peptidase IV/CD26

Citrullination and Proteolytic Processing of Chemokines by Porphyromonas gingivalis

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