Cleavage of the CD11b extracellular domain by the leukocyte serprocidins is critical for neutrophil detachment during chemotaxis

Abstract The β2-integrin CD11b/CD18 mediates the firm adhesion of neutrophils (PMNs) to epithelial monolayers, a key step in PMN transepithelial migration. To complete the transmigration process, adherent PMNs must detach from epithelial monolayer surfaces to move forward. The mechanism that governs the detachment of adherent PMNs, however, is not clear. Here, we present evidence that cleavage of the CD11b extracellular domain containing the ligand-binding I-domain by 3 structural and functional related serine proteases (elastase, proteinase-3 and cathepsin G) serves as a novel mechanism for PMN detachment after the initial cell adhesion. Kinetic studies showed that the cleavage of CD11b is positively correlated with PMN detachment and subsequent transmigration. Moreover, the results demonstrated that elastase, proteinase-3 and cathepsin G all cleaved the purified, functionally active form of CD11b in a pattern similar to the CD11b shedding that occurs during PMN transmigration. Their cleavage sites on purified CD11b were located at 761Thr-Ala762 (elastase/proteinase-3) and 760Phe-Thr761 (cathepsin G), respectively. CD11b cleavage and PMN detachment and chemotaxis, were impaired in elastase/cathepsin G–deficient Beige mice; this defect could be restored by the addition of extracellular elastase. By illustrating CD11b shedding by elastase, proteinase-3 and cathepsin G as a novel mechanism for PMN detachment, our study provides novel therapeutic targets for controlling inflammation.

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Cathepsin G, a leukocyte protease, activates coagulation factor VIII

Thrombosis and Haemostasis ◽

10.1160/th07-08-0495 ◽

2008 ◽

Vol 99 (01) ◽

pp. 44-51 ◽

Cited By ~ 10

Author(s):

Diana Rozenshteyn ◽

Andrew J Gale

Keyword(s):

Disulfide Bond ◽

Active Form ◽

Coagulation Factor ◽

Cathepsin G ◽

Cleavage Sites ◽

Subunit Dissociation ◽

Thrombin Cleavage ◽

Partial Activation ◽

Activated Platelets ◽

A Minor

SummaryNeutrophils and monocytes express cathepsin G and can also bind to activated platelets, thus they can be localized to the site of active coagulation. Previous studies have suggested that cathepsin G inactivated coagulation factorVIII (FVIII) and was thus anticoagulant. But other studies have indicated procoagulant functions for cathepsin G in activation of coagulation factorV or activation of platelets among other possible mechanisms. Therefore, it remains unclear if cathepsin G is anticoagulant or procoagulant. We investigated the effects of human neutrophil cathepsin G on FVIII/VIIIa. Cathepsin G activates FVIII to a partially active form while having only a minor inactivating effect on thrombin- activated FVIIIa. This inactivation is mostly due to decreased stability of FVIIIa since a disulfide bond that prevents A2 subunit dissociation from FVIIIa prevents any loss of activity due to cathepsin G proteolysis. FVIII that has been cleaved by cathepsin G can still be activated by thrombin if A2 subunit dissociation is prevented. Cathepsin G cleavages of FVIII are limited to a few specific sites that are mostly located near known activating and inactivating cleavage sites. Cathepsin G cleavage sites near to thrombin cleavage sites likely contribute to the partial activation of FVIII. Therefore, it is possible that cathepsin G from neutrophils and monocytes may provide some pro-coagulant effect by activating FVIII.

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Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis

Blood ◽

10.1182/blood-2002-06-1734 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1752-1758 ◽

Cited By ~ 78

Author(s):

Frank El Ouriaghli ◽

Hiroshi Fujiwara ◽

J. Joseph Melenhorst ◽

Giuseppe Sconocchia ◽

Nancy Hensel ◽

...

Keyword(s):

Negative Feedback ◽

Neutrophil Elastase ◽

Serine Proteases ◽

Cathepsin G ◽

Proteinase 3 ◽

Gm Csf ◽

Cd34 Cells ◽

Macrophage Colony ◽

Serum Free Suspension

There is evidence that neutrophil production is a balance between the proliferative action of granulocyte–colony-stimulating factor (G-CSF) and a negative feedback from mature neutrophils (the chalone). Two neutrophil serine proteases have been implicated in granulopoietic regulation: pro–proteinase 3 inhibits granulocyte macrophage–colony-forming unit (CFU-GM) growth, and elastase mutations cause cyclic and congenital neutropenia. We further studied the action of the neutrophil serine proteases (proteinase 3, elastase, azurocidin, and cathepsin G) on granulopoiesis in vitro. Elastase inhibited CFU-GM in methylcellulose culture. In serum-free suspension cultures of CD34+ cells, elastase completely abrogated the proliferation induced by G-CSF but not that of GM-CSF or stem cell factor (SCF). The blocking effect of elastase was prevented by inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride (PMSF) or heat treatment. When exposed to enzymatically active elastase, G-CSF, but not GM-CSF or SCF, was rapidly cleaved and rendered inactive. These results support a role for neutrophil elastase in providing negative feedback to granulopoiesis by direct antagonism of G-CSF.

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Local structural plasticity of the Staphylococcus aureus evasion protein EapH1 enables engagement with multiple neutrophil serine proteases

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013601 ◽

2020 ◽

Vol 295 (22) ◽

pp. 7753-7762 ◽

Cited By ~ 1

Author(s):

Timothy J. Herdendorf ◽

Daphne A. C. Stapels ◽

Suzan H. M. Rooijakkers ◽

Brian V. Geisbrecht

Keyword(s):

Staphylococcus Aureus ◽

Active Site ◽

Neutrophil Elastase ◽

Serine Proteases ◽

Noncovalent Complex ◽

Structural Plasticity ◽

Binding Mode ◽

Cathepsin G ◽

Proteinase 3 ◽

High Affinity

Members of the EAP family of Staphylococcus aureus immune evasion proteins potently inhibit the neutrophil serine proteases (NSPs) neutrophil elastase, cathepsin-G, and proteinase-3. Previously, we determined a 1.8 Å resolution crystal structure of the EAP family member EapH1 bound to neutrophil elastase. This structure revealed that EapH1 blocks access to the enzyme's active site by forming a noncovalent complex with this host protease. To determine how EapH1 inhibits other NSPs, we studied here the effects of EapH1 on cathepsin-G. We found that EapH1 inhibits cathepsin-G with a Ki of 9.8 ± 4.7 nm. Although this Ki value is ∼466-fold weaker than the Ki for EapH1 inhibition of neutrophil elastase, the time dependence of inhibition was maintained. To define the physical basis for EapH1's inhibition of cathepsin-G, we crystallized EapH1 bound to this protease, solved the structure at 1.6 Å resolution, and refined the model to Rwork and Rfree values of 17.4% and 20.9%, respectively. This structure revealed a protease-binding mode for EapH1 with cathepsin-G that was globally similar to that seen in the previously determined EapH1–neutrophil elastase structure. The nature of the intermolecular interactions formed by EapH1 with cathepsin-G differed considerably from that with neutrophil elastase, however, with far greater contributions from the inhibitor backbone in the cathepsin-G–bound form. Together, these results reveal that EapH1's ability to form high-affinity interactions with multiple NSP targets is due to its remarkable level of local structural plasticity.

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Defective Expression of Neutrophil Serine Proteases in Myeloid Progenitors of Congenital Neutropenia Patients Carrying Either ELA2 or HAX1 Mutations.

Blood ◽

10.1182/blood.v110.11.3299.3299 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3299-3299 ◽

Cited By ~ 2

Author(s):

Julia Skokowa ◽

John-Paul Fobiwe ◽

Dan Lan ◽

Manuela Germeshausen ◽

Karl Welte

Keyword(s):

Mrna Expression ◽

Neutrophil Elastase ◽

Cathepsin D ◽

Serine Proteases ◽

Cathepsin G ◽

Proteinase 3 ◽

Congenital Neutropenia ◽

Expression Levels ◽

Patient Groups ◽

Mrna Expression Levels

Abstract Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis with two major types of inheritance: autosomal dominant CN defined by mutations in ELA2 gene encoding neutrophil elastase (NE) (Horwitz M., et al., Nat Genet.1999;23:433) and autosomal recessive CN (including Kostmann syndrome) carrying HAX-1 mutations (Klein C., et al., Nat Genet.2007;39:86), both characterized by a maturation arrest of granulopoiesis at the level of promyelocytes. In the present study we aimed to evaluate the expression profile of genes specifically expressed in the CD33+ bone marrow promyelocytes of both patient groups harbouring ELA2 or HAX1 mutations. In healthy individuals mRNA expression levels of neutrophil serine proteases (neutrophil elastase (ELA2), cathepsin G, cathepsin D, proteinase 3 and azurocidin) as well as of myeloperoxidase (MPO) and defensins reached highest levels in the azurophil granules at the promyelocytic stage of neutrophil differentiation (Borregaard N., et al., Curr Opin Hematol.2001;8:23). We found downregulation of mRNA expression levels of ELA2 (8.9 fold), cathepsin G (7.6 fold), cathepsin D (11.2 fold), proteinase 3 (9.2 fold) and defensin B1 (6.5 fold) in both groups of CN patients (with ELA2 or HAX1 mutations), in comparison to G-CSF-treated patients with idiopathic neutropenia (IN) and G-CSF-treated healthy controls. In contrast, there were no difference in mRNA expression levels of azurocidin and only slight decrease in the expression of MPO mRNA in CN patients. Additionally, we found significantly reduced protein levels of neutrophil elastase (NE) in plasma of CN patients irrespective of “ELA2 or HAX1” inheritance, in comparison to cyclic neutropenia (CyN) patients, IN patients and G-CSF-treated healthy controls. Taken together, both ELA2 and HAX1 mutations are associated with defective expression of neutrophil serine proteases such as NE, cathepsin G, cathepsin D, proteinase 3 as well as of defensin B1 in CD33+ myeloid progenitor cells of CN patients, suggesting a common pathway for both patient groups. Intriguingly, ELA2 expression is directly regulated by LEF-1, suggesting that abrogated LEF-1 expression in CN promyelocytes (Skokowa J., et al., Nat. Med.2006;12:1191) may be responsible for defective serine proteases expression in both groups, since all are regulated by a similar mechanism.

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Specific Inhibition of Thrombin-Induced Cell Activation by the Neutrophil Proteinases Elastase, Cathepsin G, and Proteinase 3: Evidence for Distinct Cleavage Sites Within the Aminoterminal Domain of the Thrombin Receptor

Blood ◽

10.1182/blood.v89.6.1944 ◽

1997 ◽

Vol 89 (6) ◽

pp. 1944-1953 ◽

Cited By ~ 86

Author(s):

Patricia Renesto ◽

Mustapha Si-Tahar ◽

Marc Moniatte ◽

Viviane Balloy ◽

Alain Van Dorsselaer ◽

...

Keyword(s):

Cleavage Site ◽

Cell Activation ◽

Human Leukocyte ◽

Cytosolic Calcium ◽

Cathepsin G ◽

Thrombin Receptor ◽

Proteinase 3 ◽

Cleavage Sites ◽

Leukocyte Elastase ◽

Cell Responses

AbstractThe aim of this study was to investigate the inhibitory effects of human leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR3) on the activation of endothelial cells (ECs) and platelets by thrombin and to elucidate the underlying mechanisms. Although preincubation of ECs with HLE or Cat G prevented cytosolic calcium mobilization and prostacyclin synthesis induced by thrombin, these cell responses were not affected when triggered by TRAP42-55, a synthetic peptide corresponding to the sequence of the tethered ligand (Ser42-Phe55) unmasked by thrombin on cleavage of its receptor. Using IIaR-A, a monoclonal antibody directed against the sequence encompassing this cleavage site, flow cytometry analysis showed that the surface expression of this epitope was abolished after incubation of ECs with HLE or Cat G. Further experiments conducted with platelets indicated that not only HLE and Cat G but also PR3 inhibited cell activation induced by thrombin, although they were again ineffective when TRAP42-55 was the agonist. Similar to that for ECs, the epitope for IIaR-A disappeared on treatment of platelets with either proteinase. These results suggested that the neutrophil enzymes proteolyzed the thrombin receptor dowstream of the thrombin cleavage site (Arg41-Ser42) but left intact the TRAP42-55 binding site (Gln83-Ser93) within the extracellular aminoterminal domain. The capacity of these proteinases to cleave five overlapping synthetic peptides mapping the portion of the receptor from Asn35 to Pro85 was then investigated. Mass spectrometry studies showed several distinct cleavage sites, ie, two for HLE (Val72-Ser73 and Ile74-Asn75), three for Cat G (Arg41-Ser42, Phe55-Trp56 and Tyr69-Arg70), and one for PR3 (Val72-Ser73). We conclude that this singular susceptibility of the thrombin receptor to proteolysis accounts for the ability of neutrophil proteinases to inhibit cell responses to thrombin.

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Cloning of cDNA for proteinase 3: a serine protease, antibiotic, and autoantigen from human neutrophils.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1709 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1709-1715 ◽

Cited By ~ 117

Author(s):

D Campanelli ◽

M Melchior ◽

Y Fu ◽

M Nakata ◽

H Shuman ◽

...

Keyword(s):

Amino Acid ◽

Serine Protease ◽

Serine Proteases ◽

Specific Activity ◽

Catalytic Triad ◽

Amino Acid Sequences ◽

Cathepsin G ◽

Human Neutrophils ◽

Predicted Amino Acid Sequence ◽

Proteinase 3

Closely similar but nonidentical NH2-terminal amino acid sequences have been reported for a protein or proteins in human neutrophils whose bioactivities is/are diverse (as a serine protease, antibiotic, and Wegener's granulomatosis autoantigen) but that share(s) several features: localization in the azurophil granules, a molecular mass of approximately 29 kD, reactivity with diisopropylfluorophosphate, and the ability to degrade elastin. We previously purified one such entity, termed p29b. Using a monospecific antibody, we have cloned from human bone marrow a cDNA encoding the complete p29b protein in its mature form, along with pre- and pro-sequences. The predicted amino acid sequence agrees closely with the NH2-terminal sequence obtained previously from purified p29b, as well as with sequences newly obtained from CNBr fragments. The primary structure is highly homologous to elastase, cathepsin G, T cell granzymes, and other serine proteases, and shares both the catalytic triad and substrate binding pocket of elastase. Hybridization of the full-length cDNA with restriction enzyme digests of human genomic DNA revealed only one fragment. This suggests that the closely related species described previously are the same, and can be subsumed by the term used for the first-described activity, proteinase 3. Proteinase 3 is more abundant in neutrophils than elastase and has a similar proteolytic profile and specific activity. Thus, proteinase 3 may share the role previously attributed to neutrophil elastase in tissue damage, and has the potential to function as an antimicrobial agent.

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Processing of Neutrophil α-Defensins Does Not Rely on Serine Proteases in Vivo

Blood ◽

10.1182/blood.v124.21.1400.1400 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1400-1400

Author(s):

Andreas Glenthoj ◽

Katrin Nickles ◽

Jack B Cowland ◽

Niels Borregaard

Keyword(s):

Human Neutrophil ◽

Serine Proteases ◽

Bone Marrow Cells ◽

Conflicts Of Interest ◽

Myeloid Cell ◽

Subcellular Fractionation ◽

Cathepsin G ◽

Proteinase 3 ◽

Processing Protease

Abstract The α-defensins human neutrophil peptides (HNPs) are the predominant antimicrobial peptides of neutrophil granules. They are synthesized in promyelocytes and myelocytes as proHNPs, but only processed and stored as mature HNPs in promyelocytes. Despite decades of search, the mechanisms underlying the posttranslational processing of neutrophil defensins remain unidentified. Thus, neither the enzyme processing proHNPs nor the localization of processing has been identified. It has long been hypothesized that proHNPs are processed by the serine proteases highly expressed in promyelocytes: Neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3), all of which have shown in vitrocapability to process recombinant proHNP into HNP. We investigated, whether serine proteases are in fact responsible for proHNP processing in human bone marrow cells and in human and murine myeloid cell lines. Subcellular fractionation of the human promyelocytic cell line PLB-985 demonstrated proHNP processing to commence in fractions containing endoplasmic reticulum. Processing of 35S-proHNP was insensitive to serine protease inhibitors. Simultaneous knockdown of NE, CG, and PR3 did not decrease proHNP processing by primary human neutrophil precursors. Furthermore, introduction of NE, CG, and PR3 into murine promyelocytic cells did not increase processing capability. Finally, two patients suffering from Papillon–Lefèvre syndrome, who lack the ability to activate neutrophil serine proteases, demonstrated normal levels of fully processed HNP in peripheral neutrophils. Contradicting earlier assumptions, our study found serine proteases dispensable for processing of proHNPs in vivo. This calls for study of other protease classes in the search for the proHNP processing protease(s). Disclosures No relevant conflicts of interest to declare.

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A rare CTSC mutation in Papillon-Lefèvre Syndrome results in abolished serine protease activity and reduced NET formation but otherwise normal neutrophil function

PLoS ONE ◽

10.1371/journal.pone.0261724 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261724

Author(s):

Felix P. Sanchez Klose ◽

Halla Björnsdottir ◽

Agnes Dahlstrand Rudin ◽

Tishana Persson ◽

Arsham Khamzeh ◽

...

Keyword(s):

Protease Activity ◽

Serine Proteases ◽

Fungal Infections ◽

Active Form ◽

Neutrophil Function ◽

Amino Acid Replacement ◽

Cathepsin G ◽

Monogenic Disease ◽

Loss Of Function ◽

Palmoplantar Hyperkeratosis

Papillon-Lefèvre Syndrome (PLS) is an autosomal recessive monogenic disease caused by loss-of-function mutations in the CTSC gene, thus preventing the synthesis of the protease Cathepsin C (CTSC) in a proteolytically active form. CTSC is responsible for the activation of the pro-forms of the neutrophil serine proteases (NSPs; Elastase, Proteinase 3 and Cathepsin G), suggesting its involvement in a variety of neutrophil functions. In PLS neutrophils, the lack of CTSC protease activity leads to inactivity of the NSPs. Clinically, PLS is characterized by an early, typically pre-pubertal, onset of severe periodontal pathology and palmoplantar hyperkeratosis. However, PLS is not considered an immune deficiency as patients do not typically suffer from recurrent and severe (bacterial and fungal) infections. In this study we investigated an unusual CTSC mutation in two siblings with PLS, a 503A>G substitution in exon 4 of the CTSC gene, expected to result in an amino acid replacement from tyrosine to cysteine at position 168 of the CTSC protein. Both patients bearing this mutation presented with pronounced periodontal pathology. The characteristics and functions of neutrophils from patients homozygous for the 503A>G CTSC mutation were compared to another previously described PLS mutation (755A>T), and a small cohort of healthy volunteers. Neutrophil lysates from patients with the 503A>G substitution lacked CTSC protein and did not display any CTSC or NSP activity, yet neutrophil counts, morphology, priming, chemotaxis, radical production, and regulation of apoptosis were without any overt signs of alteration. However, NET formation upon PMA-stimulation was found to be severely depressed, but not abolished, in PLS neutrophils.

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Olfactomedin 4 Down-Regulates Neutrophil Killing of Gram-Positive and Gram-Negative Bacteria.

Blood ◽

10.1182/blood.v116.21.3777.3777 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3777-3777

Author(s):

Wenli Liu ◽

Ming Yan ◽

Yueqin Liu ◽

William G Coleman ◽

Griffin P. Rodgers

Keyword(s):

Neutrophil Elastase ◽

Serine Proteases ◽

Cathepsin G ◽

Proteinase 3 ◽

Gram Negative Bacteria ◽

Wild Type ◽

Gram Negative ◽

Cathepsin C ◽

E Coli ◽

Deficient Mice

Abstract Abstract 3777 Introduction: Olfactomedin 4 (OLFM4) is a member of olfactomedin-related glycoprotein family, which is specifically expressed in neutrophils and gastrointestinal tract. OLFM4 expression is upregulated in gastrointestinal cancer and inflammatory diseases such as chronic inflammatory bowel disease and Helicobacter pylori infection. It has been shown that OLFM4 is a target gene of NF-kB and Notch pathways and that OLFM4 down-regulates innate immunity to H. pylori infection. However, its potential biological functions in neutrophils still remain to be defined. The goal of this study is to determine whether OLFM4 is involved in the bactericidal activity of neutrophils using an OLFM4 deficient mouse model. Results: 1. OLFM4 expression in neutrophils is upregulated in response to Staphylocococus aureus (Gram positive) and Escherichia coli (Gram negative) bacteria. 2. We have shown that neutrophils from OLFM4 deficient mice have increased intracellular killing of S. aureus and E. coli bacteria in vitro. 3. The OLFM4 deficient mice displayed enhanced bacterial clearance in vivo when the mice were challenged with intra-peritoneal injection of S. aureus and E. coli. 4. To elucidate the molecular mechanisms that mediate these effects, we performed a yeast 2-hybrid screen and found that OLFM4 interacts with cathepsin C (dipeptidyl peptidase I or DPPI), a lysosomal cysteine protease that has a degraditive function as an exopeptidase and is essential for activation of neutrophil granule-associated serine proteases including neutrophil elastase, cathepsin G and proteinase 3. The direct association of OLFM4 with cathepsin C was confirmed in human primary neutrophils. 4. We have demonstrated that OLFM4 is a direct substrate of DPPI and inhibits DPPI activity in transfected 293T cells. 5. The cathepsin C activity in neutrophils from OLFM4 deficient mice was significantly higher than that in neutrophils from wild-type littermate mice in the absence or presence of bacterial infection, suggesting that OLFM4 is an endogenous inhibitor of cathepsin C in neutrophils. 6. We have also demonstrated increased activities of neutrophil elastase, cathepsin G and proteinase 3 (whose processing and maturity require cathepsin C activity) in OLFM4 deficient neutrophils compared with wild-type neutrophils. 7. Activation of NADPH oxidase, myeloperoxidase (MPO) activity, and neutrophil phagocytosis were not altered in OLFM4 deficient neutrophils compared with wild-type neutrophils. Conclusion: These results suggest that OLFM4 is an important regulator of neutrophil bacterial killing activity via negative regulation of cathepsin C activity and its down stream granule-associated serine proteases. Disclosures: No relevant conflicts of interest to declare.

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Potent and Broad but not Unselective Cleavage of Cytokines and Chemokines by Human Neutrophil Elastase and Proteinase 3

International Journal of Molecular Sciences ◽

10.3390/ijms21020651 ◽

2020 ◽

Vol 21 (2) ◽

pp. 651 ◽

Cited By ~ 1

Author(s):

Zhirong Fu ◽

Srinivas Akula ◽

Michael Thorpe ◽

Lars Hellman

Keyword(s):

Mast Cell ◽

Neutrophil Elastase ◽

Human Neutrophil ◽

Serine Proteases ◽

General Pattern ◽

Neutrophil Activation ◽

Cathepsin G ◽

Human Neutrophil Elastase ◽

Proteinase 3 ◽

Cytokines And Chemokines

In two recent studies we have shown that three of the most abundant human hematopoietic serine proteases—mast cell chymase, mast cell tryptase and neutrophil cathepsin G—show a highly selective cleavage of cytokines and chemokines with a strong preference for a few alarmins, including IL-18, TSLP and IL-33. To determine if this is a general pattern for many of the hematopoietic serine proteases we have analyzed the human neutrophil elastase (hNE) and human proteinase 3 (hPR-3) for their cleavage of a panel of 69 different human cytokines and chemokines. Our results showed that these two latter enzymes, in sharp contrast to the two previous, had a very potent and relatively unrestrictive cleavage on this panel of targets. Almost all of these proteins were cleaved and many of them were fully degraded. In light of the proteases abundance and their colocalization, it is likely that together they have a very potent degrading activity on almost any protein in the area of neutrophil activation and granule release, including both foreign bacterial or viral proteins as well as various self-proteins in the area of inflammation/infection. However, a few very interesting exceptions to this pattern were found indicating a high resistance to degradation of some cytokines and chemokines, including TNF-α, IL-5, M-CSF, Rantes, IL-8 and MCP-1. All of these are either important for monocyte-macrophage, neutrophil or eosinophil proliferation, recruitment and activation, suggesting that cytokines/chemokines and proteases may have coevolved to not block the recruitment of monocytes–macrophages, neutrophils and possibly eosinophils during an inflammatory response involving neutrophil activation.

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