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Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Recombinant chemerin and prochemerin were obtained as described (5). Purified HLE, mast cell chymase and CG were obtained from Calbiochem. Proteinase 3 was purchased from Elastin Products. The purity of HLE and CG was 
95% as determined by SDS-PAGE, according to the manufacturer. The other proteases, dextran T-500, cytochalasin B, fMLP, LPS, and protease inhibitors were purchased from Sigma-Aldrich. Secretory leukocyte protease inhibitor (SLPI) was purchased from R&D Systems.
Aequorin-based functional assay
Intracellular Ca2+ release in a CHO-K1 cell line expressing the human ChemR23 receptor was measured as described (5, 10) by a functional assay based on the luminescence of mitochondrial aequorin (14). Results were expressed as relative light units or as a percentage of the endogenous response to 20 µM ATP.
Isolation of human neutrophils from peripheral blood
Human neutrophils were isolated from healthy donors. Briefly, after sedimentation with 3% dextran T-500 (Sigma-Aldrich) in isotonic NaCl, the leukocyte-rich supernatant was pelleted, resuspended in saline, and centrifuged at 400 x g for 40 min on Lymphoprep (Axis-Shield), for the removal of lymphocytes and monocytes. Remaining erythrocytes were lysed by addition of 1 vol of 0.2% NaCl, and tonicity was restored after 30 s by the addition of 1 vol of 1.6% NaCl. Cells were washed once and resuspended in the adequate buffer. With the exception of dextran sedimentation, all steps were conducted at 4°C. Water was checked as endotoxin- and pyrogen-free.
Neutrophil-conditioned medium preparation
PMN (5 x 105 cells/ml in HBSS with or without 0.01% BSA) were incubated for 30 min at 37°C with 5 µg/ml cytochalasin B and 0.5 µM fMLP. Alternatively, the cells were incubated for 5 min at 37°C with 1 ng/ml LPS, then for 30 min with 10 nM fMLP. Following stimulation, cells were centrifuged, and supernatants were used in the prochemerin conversion assay.
Assay of prochemerin-processing enzyme activity in neutrophil-conditioned medium
Recombinant human prochemerin (220 nM) was incubated in neutrophil-conditioned medium containing 0.01% BSA for 30 min at 37°C before being assayed for activation of ChemR23-expressing CHO-K1 cells. For the testing of enzyme inhibitors, the media were preincubated with inhibitors for 30 min at 37°C, after which 220 nM prochemerin was added and incubated for another 30 min at 37°C before being assayed. Potential interference of inhibitors with the aequorin assay was evaluated by testing the inhibitors alone and testing the ability of 5 nM chemerin to stimulate the chemerinR-expressing cell line in the presence of inhibitors.
Assay of recombinant prochemerin conversion by human proteases
Recombinant human prochemerin (44 nM) was incubated for 15 min at 37°C in 25 mM HEPES buffer, pH 7.4, containing 0.01% BSA and various amounts of purified human proteases (300 ng/ml to 3 pg/ml), before being assayed for activation of ChemR23-expressing CHO-K1 cells.
Monoclonal Abs against prochemerin or chemerin
BALB/c mice were injected with human recombinant chemerin or the prochemerin COOH-terminal octapeptide FSKALPRS. Sera were tested by ELISA, and immune mice were used to generate mAbs by standard hybridoma technology, using the NSO myeloma cell line (15). The 5H6 mAb was shown to recognize specifically prochemerin but no mature chemerin, whereas the 7F6 mAb recognizes both active chemerin and prochemerin.
Western blot analysis
Recombinant human prochemerin (10 ng) was incubated for 30 min at 37°C in 25 mM HEPES buffer, pH 7.4, containing 0.01% BSA in the presence of 0.1 ng of purified human CG, elastase, or both, and the reaction was stopped by mixing with SDS-PAGE sample buffer. Proteins were separated by SDS-PAGE on a 15% polyacrylamide gel for 
4 h and electrotransferred to nitrocellulose membranes. The blots were soaked into a solution of 2% skim milk, then incubated for 2 h with the 7F6 mAb, recognizing both active chemerin and prochemerin (dilution 1/3000), or with the anti-prochemerin 5H6 mAb (dilution 1/30,000). Bound Abs were detected using a peroxidase-labeled anti-mouse IgG and a chemiluminescence kit (Amersham). Quantitative gel analysis was performed using a GS-800 densitometer and Quantity One software (Bio-Rad).
Mass spectrometry analysis
Prochemerin (44 nM) was incubated for 30 min at 37°C in a BSA-free HEPES buffer in the presence of purified HLE or CG (15 ng/ml), and the reaction was stopped by heating at 95°C. Samples were then adjusted to pH 8.0 and incubated with 250 ng of trypsin (Promega) for 1 h at 37°C. The digested peptides were purified by solid-phase extraction (C18 StageTips; Proxeon Biosystems), eluted onto a metallic MALDI target, dried and mixed with 1.5 µl of matrix mix (2 mg/ml 2,5-dihydroxybenzoic acid and 10 mg/ml 
-cyano-4-hydroxycinnamic acid, 2 mM fucose, 5 mM ammonium acetate). For the tests with PMN-conditioned media, prochemerin (220 nM) was incubated in a BSA-free medium for 1 h at 37°C. Following trypsin digestion, the peptides were separated onto a C18 reverse-phase 1 x 50 mm column (Vydac), which was submitted to a 5–95% CH3CN gradient at a rate of 2.5%/min in 0.1% trifluoroacetic acid. Fraction collection was adjusted in a manner to eluate the three potential COOH-terminal peptides of chemerin or prochemerin in a single fraction for direct mass spectrometry analysis. The HPLC fractions were vacuum-dried and then resuspended in 1.5 µl of matrix mix onto the MALDI target. Mass spectrometry analysis was performed on a Q-TOF Ultima Global mass spectrometer equipped with a MALDI source (Micromass) and calibrated using the monoisotopic masses of tryptic and chymotryptic peptides from BSA. Ionization was achieved using a nitrogen laser (337-nm beam, 10 Hz) and acquisitions were performed in a V mode reflectron position. Microsequencing was obtained after argon-induced fragmentation after selection of the parent ion.
Ca2+ mobilization assay
Monocyte-derived DCs, generated as previously described (5), were loaded with 5 µM fura-2 (Molecular Probes) for 30 min at 37°C in the dark (107 cells/ml in HBSS without phenol red but containing 0.1% BSA). The loaded cells were washed twice, resuspended at 106 cells/ml, kept for 15 min at 4°C in the dark, and transferred into the quartz cuvette of a luminescence spectrometer LS50B (PerkinElmer). Ca2+ mobilization in response to human chemerin was measured by recording the ratio of fluorescence emitted at 510 nm after sequential excitation at 340 and 380 nm.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Previous studies have demonstrated that the proteolytic processing of prochemerin into chemerin is essential for the APC chemotactic activity of the protein (5, 10). This processing affects the C-terminal end of the protein, located after the last cysteine involved in the disulfide bonds that presumably stabilize the cystatin fold domain of this secreted protein. Given the established role of PMN as the predominant migrating cell during the early stages of inflammation, we investigated whether conditioned media from purified neutrophils have the ability to convert prochemerin into biologically active chemerin. The neutrophil-mediated inflammatory response is dependent on the release of the content of their cytoplasmic granules upon activation, a mechanism termed degranulation (16). Human PMN were isolated from peripheral blood, and stimulated with potent inducers of degranulation, cytochalasin B and fMLP or LPS and fMLP (17). Human recombinant prochemerin was incubated with conditioned media, and its conversion into chemerin was tested by measuring the activation of the chemerinR using an aequorin-based calcium mobilization assay. Fig. 1a shows that incubation of prochemerin with conditioned media from unstimulated PMN for 30 min resulted in a weak specific activity on chemerinR, reflecting basal proteolytic conversion of the precursor. This specific activity was however significantly increased after induction of PMN degranulation by cytochalasin B and fMLP, and a similar activation of the chemerinR was observed when PMN were primed with LPS and challenged with fMLP (Fig. 1b).
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Purified CG and HLE convert prochemerin into active chemerin
To further examine whether neutrophil-derived serine proteases are involved in chemerin generation, we next tested the ability of purified CG, HLE, and proteinase 3 to convert prochemerin into its active form. Prochemerin was incubated for 15 min with the proteases (3 pg/ml to 300 ng/ml), and the reaction mixtures tested for their activity on chemerinR. In parallel, we also tested a range of other human serine proteases, including plasmin, urokinase, thrombin, kallikrein, and mast cell chymase. Fig. 2a shows that plasmin, urokinase, thrombin, kallikrein, chymase, and proteinase 3 did not promote the generation of bioactive chemerin, whereas CG and HLE efficiently converted prochemerin, down to low enzyme concentrations (0.3 ng/ml). In control experiments performed in the absence of prochemerin, it was verified that none of the enzymes displayed activity on chemerinR by themselves (data not shown). Moreover, Western blot analysis was used to determine whether the conversion of prochemerin into active chemerin involved the C-terminal part of the precursor, as expected from our previous observations (5, 10). mAbs were generated to discriminate the unprocessed prochemerin from chemerin activated by COOH-terminal truncation. As shown in Fig. 2b, both proteins were immunodetected as a doublet presenting an apparent m.w. of 17,000. The 5H6 mAb, raised against the C-terminal octapeptide of prochemerin detects prochemerin but not chemerin. Maturation of prochemerin with CG, HLE or both, led to a decrease of the immunoreactivity, as a result of the loss of the C-terminal epitope recognized by the 5H6 mAb. Quantitative analysis revealed a decrease of the signal by 20, 45, and 80% for CG, HLE, and both enzymes, respectively. The apparent size of the protein, as well as its total amount following detection by the 7F6 mAb that recognizes both active chemerin and prochemerin, were not affected by the proteolytic treatment. These observations indicate that the C-terminal end of prochemerin is the only target site of CG and HLE and that these two proteases do not cleave prochemerin in its other domain. Altogether, these results demonstrate that, among the three neutrophil-derived serine proteases, CG and HLE have both the ability to generate active intact chemerin from its precursor and are most probably both involved in neutrophil-induced chemerin generation.
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CG and HLE are enzymes that display different cleavage site specificities: CG was described to hydrolyze peptide bonds involving an aromatic residue, whereas HLE preferentially cleaves bonds downstream to small, nonpolar residues, particularly valine or serine (18). To determine the precise nature of the active chemerin forms generated by these enzymes, prochemerin was incubated with 0.5 ng of CG or HLE, and the products were analyzed by mass spectrometry, after trypsin treatment, with an emphasis on the C-terminal end of the protein. Proteinase 3, which does not induce bioactive chemerin generation, was also used in this assay. As expected, in the absence of proteases, a tryptic peptide with a molecular mass of 2031.92 Da was observed, corresponding to amino acids 141 to 158 of unprocessed prochemerin (Fig. 3a). Following elastase treatment, an additional nontryptic peak appeared, with a molecular mass of 1903.82 Da. Fragmentation-induced microsequencing demonstrated that this peak corresponded to prochemerin cleavage after the serine in position 157 (Fig. 3b). This C-terminal end corresponds to the major natural bioactive form of chemerin previously purified from human ascitic fluid (5). Interestingly, after incubation with CG, the 1903.82-Da peptide was not recovered, but another nontryptic peak of 1816.79 Da was found, resulting from prochemerin cleavage after the phenylalanine in position 156 (Fig. 3c). As expected, these two peptides were not observed following prochemerin incubation with proteinase 3 (Fig. 3, b and c). Our data demonstrate therefore that in vitro processing of prochemerin by neutrophil-derived serine proteases results in the production of two distinct C-terminal variants of bioactive chemerin. Although HLE cleaves the Ser157-Lys158 bond, CG cleaves the Phe156-Ser157 bond, in agreement with the preferred cleavage sites reported previously for these two enzymes. It is worth noting that none of the other serine proteases tested in the functional assay was able to generate any of these two peptides (data not shown). Also, thorough analysis of the entire mass spectrum resulting from prochemerin processing by CG and HLE did not identify additional cleavage sites for these two proteases, in agreement with the Western blotting experiments as described (data not shown).
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We next examined whether CG and HLE are both responsible for the neutrophil-mediated chemerin generation ex vivo. Prochemerin was incubated with conditioned medium from neutrophils activated by cytochalasin B and fMLP, assayed for biological activity on the chemerinR, and analyzed by mass spectrometry. To avoid contamination of the spectrum with a large number of signals resulting from the proteolysis of the N-terminal domain of prochemerin and other proteins present in the medium, peptides generated by tryptic digestion were first separated by reverse-phase chromatography. The three potential COOH-terminal peptides of prochemerin or chemerin were shown to elute at the same elution time and the corresponding fraction was analyzed by mass spectrometry. As shown in Fig. 4a, both the 1903.82- and 1816.79-Da peptides, corresponding respectively to HLE and CG cleavage, could clearly be detected. Natural inhibitors of neutrophil serine proteases are found in plasma, including the SLPI, which act as a specific inhibitor of both CG and HLE (18). The effect of SLPI was evaluated on PMN-induced chemerin generation. Mass spectrometry analysis showed that the signals corresponding to the two active variants of chemerin were significantly decreased following pretreatment with SLPI (Fig. 4a). Furthermore, in the functional assay, chemerinR activation was abolished when SLPI (1 µM) or plasma (20%) were added to the conditioned medium of cytochalasin B/fMLP-activated PMN (Fig. 4b). Together, these data clearly demonstrate that neutrophil-mediated chemerin generation is performed by CG and HLE, both released in the extracellular milieu following neutrophil degranulation. The two chemerin variants generated by neutrophils are identical with the forms identified initially in human ascitic fluids (5, 10). These variants, characterized by mass spectrometry following HPLC purification, as previously described (5), were shown to activate human monocyte-derived immature DCs, for which the expression of ChemR23 has been established (Fig. 4c).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The involvement of neutrophils in the generation of chemerin is an interesting observation for the understanding of chemerin functions in vivo. As phagocytes recruited in the early stages of an inflammatory reaction, neutrophils represent the first line of defense against pathogenic invaders, and are therefore essential effector cells of innate immunity (22). The activation of neutrophils leads to their degranulation and to the release of microbicidal products and other agents involved in host defense mechanisms, including reactive oxygen species, cationic peptides, eicosanoids, and proteolytic enzymes. Neutrophils can also contribute to the development of adaptive immunity, as a number of products prestored in neutrophil granules were shown to attract cells involved in the initiation of specific immune responses, including DCs. As examples, the microbicidal peptides defensins are chemotactic for immature DCs and T lymphocytes (23), the human cathelicidin LL-37 recruits PMNs, monocytes, and T cells (12), whereas CG and azurocidin were shown to be chemotactic for PMN and mononuclear cells (24).
HLE and CG constitute, with proteinase 3, the three major serine proteases of the azurophil granules of neutrophils. CG and HLE are also found in the granules of monocytes, but in quantitative terms, neutrophils constitute by far the main source (25, 26). The main physiological function of these proteases is commonly thought to be intralysosomal degradation of engulfed cell debris or microorganisms. However, following neutrophil stimulation, CG, HLE, and proteinase 3 are rapidly released from cytoplasmic granules into the extracellular space, and evidence has accumulated over the past few years suggesting that HLE and CG also play crucial roles in extracellular proteolytic processes at inflammatory sites (27). Activation of neutrophils has also been shown to result in an increase in the catalytically active membrane-bound form of the proteinases on the neutrophil cell surface (27, 28, 29). The functional relevance of the neutrophil granules content in host defense mechanisms is illustrated by Chediak-Higashi syndrome, a rare genetic disease characterized by a defect in azurophil granules release. These patients suffer from severe bacterial infections and often develop an atypical lymphoproliferative syndrome (30). If neutrophil-derived proteases constitute fundamental components of physiological immune responses, the excessive, prolonged, or inappropriate activity of these enzymes can also play a pivotal role in physiopathological events leading to serious tissue damage and dysfunction (31, 32).
The chemerin form generated by HLE corresponds to the major natural active form purified originally from human ascitic fluid (5). Interestingly, the variant generated by CG was also found, although less abundantly, in the human ascitic fluid, and was shown to be active from a previous structure-function analysis (10). We have indeed demonstrated that a nonapeptide derived from the chemerin C terminus, 149YFPGQFAFS157 displayed biological activity on the chemerin receptor similar to that of the full-size protein. Removal of Ser157 was relatively well tolerated. Removal of two amino acids or addition of a single amino acid at the C terminus of this peptide abolished its biological activity, indicating that very precise prochemerin processing is required for the generation of active chemerin. Our results provide therefore the first evidence that two different bioactive C-terminal chemerin variants can specifically be produced by primary immune cells, i.e., human neutrophils.
A remaining question is how prochemerin synthesis is regulated in vivo. Prochemerin transcripts have been detected in most human tissues tested, whereas no transcripts were found in peripheral blood leukocyte populations (5). In addition, high amounts of active chemerin were found in a diverse set of human inflammatory fluids (5). Although further studies will be necessary to understand the events that regulate prochemerin secretion in vivo, the available data suggest that inactive prochemerin might be produced constitutively by tissues in basal conditions. It would be converted into bioactive chemerin only in inflammatory conditions, following degranulation of infiltrating neutrophils, contributing to the enhancement of an Ag-specific immune response (Fig. 5). High amounts of CG and HLE are released upon neutrophil degranulation. Up to 1 µg of CG was reported to be released per million of activated PMN (33), and stimulated PMNs have been shown to have 100 ng of cell surface HLE or CG per 106 cells (27, 34). According to our results in vitro, this is by far sufficient for proteolytic conversion of prochemerin into active chemerin. The conversion of prochemerin by unstimulated PMN is attributed to a partial activation of the cells during the purification process. It is however not excluded that other proteases might contribute to the activation of chemerin in vivo. In this context, the involvement of proteases of the coagulation cascade has been suggested recently (8).
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Acknowledgments |
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Disclosures |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Footnotes |
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1 This work was supported by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister’s Office, Science Policy Programming, Grant LSHB-CT-2003-503337 from the LifeSciHealth Programme of the European Community, the Fonds de la Recherche Scientifique Médicale of Belgium, Télévie, Fortis, and the Fondation Médicale Reine Elisabeth (to M.P.). The scientific responsibility is assumed by the authors. V.W. was recipient of a grant from the First-Industrie Program of the Walloon Region and Télévie. D.C. is a Research Associate of the Belgian Fonds National de la Recherche Scientifique. 
2 Address correspondence and reprints requests to Dr. Marc Parmentier, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, B-1070 Bruxelles, Belgium. E-mail address: mparment{at}ulb.ac.be
3 Abbreviations used in this paper: DC, dendritic cell; HLE, human leukocyte elastase; PMN, polymorphonuclear cell; CG, cathepsin G; SLPI, secretory leukocyte protease inhibitor.
Received for publication January 27, 2005. Accepted for publication April 15, 2005.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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-Defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286: 525-528.1-antitrypsin in cancer development and progression. Lancet Oncol. 5: 182-190.[Medline]
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