Serine Protease Cathepsin G Regulates Adhesion-Dependent Neutrophil Effector Functions by Modulating Integrin Clustering

Raptis, Sofia Z.; Shapiro, Steven D.; Simmons, Pamela M.; Cheng, Alec M.; Pham, Christine

doi:10.1016/j.immuni.2005.03.015

Cited by 69 publications

(74 citation statements)

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“…Alpha-1-antichymotrypsin 3 plays a significant role in the inhibition of serine proteases such as cathepsin G, which is released by granulocytes during inflammation [25]. It has been shown that cathepsin G regulates the ability of PMN to stimulate other immune cells, triggering the start of local inflammatory processes [41]. Thus, low levels of alpha-1-antichymotrypsin would lead to increased presence of cathepsin G and, presumably, increase inflammation.…”

Section: Discussionmentioning

confidence: 99%

Glycoprotein analysis of porcine bronchoalveolar lavage fluid reveals potential biomarkers corresponding to resistance toActinobacillus pleuropneumoniaeinfection

D¹,

Buettner²,

Naim³

et al. 2009

Vet. Res.

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-Biomarkers facilitating both pathogen-independent diagnosis of respiratory health and breeding selection of pigs with increased resistance to respiratory tract infections would be of considerable interest to the pig industry. Following this concept we performed a comparative glycoproteome analysis of bronchoalveolar lavage fluid (BALF) from healthy pigs and pigs 4 days (acute) and 20 days (chronic) after an experimental infection with Actinobacillus pleuropneumoniae. In order to identify possible differences in BALF glycoprotein patterns we investigated pigs of three different breeding lines (German Landrace, Piétrain, Hampshire). In total, 12 glycosylated proteins (alpha-1-acid glycoprotein, fetuin A, properdin, haptoglobin precursor, haptoglobin, hemoglobin, hyaluronidase, inter-alpha-trypsin inhibitor family heavy chain-related protein, alpha-1-antichymotrypsin 3, pulmonary surfactant-associated protein D (SP-D), transferrin, and alpha-1B-glycoprotein) were identified as being differentially expressed depending on the health status of the animal. Fetuin A levels were consistently low in chronically infected pigs thereby being a potential marker for chronic infection. Hyaluronidase levels were consistently high in all pigs after experimental infection independent on isolation of the pathogen thereby being a potential marker for previous pathogen contact and latent infection. High levels of fetuin A as well as low levels of haptoglobin and pulmonary SP-D correlated with the absence of lung lesions in pigs of the Hampshire breeding line, implying a potential application as selection markers for breeding programmes.porcine respiratory disease / glycoprotein analysis / bronchoalveolar lavage fluid / biomarker

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Section: Discussionmentioning

confidence: 99%

Glycoprotein analysis of porcine bronchoalveolar lavage fluid reveals potential biomarkers corresponding to resistance toActinobacillus pleuropneumoniaeinfection

D¹,

Buettner²,

Naim³

et al. 2009

Vet. Res.

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“…Neutrophils were isolated from bone marrow by a discontinuous Percoll gradient, as previously described (29). Neutrophil purity was consistently 80-90% as assessed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Pagano

Bartoli

Ennis

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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120

121

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Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease critical for the activation of granule-associated serine proteases, including neutrophil elastase, cathepsin G, and proteinase 3. DPPI and granule-associated serine proteases have been shown to play a key role in regulating neutrophil recruitment at sites of inflammation. It has recently been suggested that neutrophils and neutrophil-associated proteases may also be important in the development and progression of abdominal aortic aneurysms (AAAs), a common vascular disease associated with chronic inflammation and destructive remodeling of aortic wall connective tissue. Here we show that mice with a loss-of-function mutation in DPPI are resistant to the development of elastase-induced experimental AAAs. This is in part because of diminished recruitment of neutrophils to the elastase-injured aortic wall and impaired local production of CXC-chemokine ligand (CXCL) 2. Furthermore, adoptive transfer of wild-type neutrophils is sufficient to restore susceptibility to AAAs in DPPI-deficient mice, as well as aortic wall expression of CXCL2. In addition, in vivo blockade of CXCL2 by using neutralizing antibodies directed against its cognate receptor leads to a significant reduction in aortic dilatation. These findings suggest that DPPI and/or granule-associated serine proteases are necessary for neutrophil recruitment into the diseased aorta and that these proteases act to amplify vascular wall inflammation that leads to AAAs. cardiovascular ͉ inflammation ͉ innate immunity ͉ proteases

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“…Increased integrin affinity for its ligands then permits enhanced ''outside-in'' integrin activation of downstream signalling pathways, leading to the secretion of chemokines and reactive oxygen intermediates, cytoskeletal remodelling and other inflammatory events. Cathepsin G-deficient neutrophils failed to trigger normal CD11b integrin clustering which in turn compromised Rac1 activation and the production of MIP-2 and reactive oxygen intermediates [72]. This phenotype could be rescued by addition of exogenous catalytically active cathepsin G. Its substrates remain to be identified, however.…”

mentioning

confidence: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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Serine Protease Cathepsin G Regulates Adhesion-Dependent Neutrophil Effector Functions by Modulating Integrin Clustering

Cited by 69 publications

References 50 publications

Glycoprotein analysis of porcine bronchoalveolar lavage fluid reveals potential biomarkers corresponding to resistance toActinobacillus pleuropneumoniaeinfection

Glycoprotein analysis of porcine bronchoalveolar lavage fluid reveals potential biomarkers corresponding to resistance toActinobacillus pleuropneumoniaeinfection

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Diverse regulatory roles for lysosomal proteases in the immune response

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