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* Department of Immunology, Parasitology and Ultrastructure, Vlaams Interuniversitair Instituut voor Biotechnologie, Vrije Universiteit Brussel, Belgium; and
Department of Immunology, University of Cape Town, Groote Schuur Hospital, South Africa
Correspondence: Dr. Gholamreza Hassanzadeh Gh., Cellular Immunology Unit, Vlaams Interuniversitair Instituut voor Biotechnologie, Vrije Universiteit Brussel, Paardenstraat 65, B-1640 Sint-Genesius-Rode, Belgium. E-mail: reza{at}bigben.vub.ac.be
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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) display molecular and biological characteristics that differ from those of classically activated macrophages (caM). Recently, we described an experimental model of murine trypanosomosis in which the early stage of infection of mice with a Trypanosoma brucei brucei variant is characterized by the development of caM, whereas in the late and chronic stages of infection, aaM develop. In the present study, we used suppression subtractive hybridization (SSH) to identify genes that are expressed differentially in aaM versus caM elicited during infection with this T. b. brucei variant. We show that FIZZ1 and Ym1 are induced strongly in in vivo- and in vitro-elicited aaM as compared with caM. Furthermore, we demonstrate that the in vivo induction of FIZZ1 and Ym1 in macrophages depends on IL-4 and that in vitro, IFN-
antagonizes the effect of IL-4 on the expression of FIZZ1 and Ym1. Collectively, these results open perspectives for new insights into the functional properties of aaM and establish FIZZ1 and Ym1 as markers for aaM.
Key Words: trypanosoma • peritoneal exudates • subtracted cDNA • RELM
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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), induced by proinflammatory molecules such as interferon- (IFN-) and lipopolysaccharide (LPS), are important players in the elimination of various pathogens [1
]. They possess antimicrobial, antiproliferative, and cytotoxic properties, partly because of their ability to secrete nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF-), interleukin (IL)-1, and IL-6 [2
]. However, the persistence or escalation of the inflammatory processes mediated by caM can result in immunopathology [3
, 4
]. Type II immune-response mediators, such as IL-4 and glucocorticoids, antagonize caM and induce the development of alternatively activated macrophages (aaM) [1
]. In aaM, inducible NO synthase (iNOS), catalyzing the production of NO and L-citrulline from L-arginine, is suppressed. Instead, aaM are characterized by an alternative, metabolic pathway of arginine, catalyzed by arginase that converts L-arginine to L-ornithine and urea [5
]. Moreover, aaM secrete anti-inflammatory mediators such as transforming growth factor-ß (TGF-ß) and IL-10 [1
]. Hence, aaM are considered to secure the balance between pro- and anti-inflammatory reactions during type I cytokine-driven inflammatory responses [1
]. In addition, it has been shown that aaM exhibit a high endo- and phagocytotic capacity [1
] and can promote angiogenesis [6
] and contribute to wound healing [7
]. However, in general, the exact functional properties of aaM in vivo remain unclear. Because aaM have been found to be associated with type II cytokine-controlled, inflammatory diseases [8
, 9
], it cannot be excluded that under these circumstances, aaM are proinflammatory and support the development of pathology. Finally, because of their ability to act as antigen-presenting cells as well as to secrete immunosuppressive and/or immunomodulatory mediators, caM and aaM can influence the development and maintenance of adaptive immune responses [2
, 10
11
12
].
The molecular differences between differentially activated macrophages have begun to be unraveled slowly. For example, expression of the three species of the Fc receptor for immunoglobulin G (IgG; FcR) was found to be induced by IFN- but inhibited by IL-4 [13
, 14
]. Conversely, the macrophage-mannose receptor [15
], 15-lipoxygenase [16
], fibronectin, and the extracellular matrix protein ßIG-H3 [7
] have been shown to be up-regulated in IL-4-induced aaM. In human macrophages, the surface markers MS-1 high molecular-weight protein (MS-1-HMWP) [17
], the scavenger receptor CD163 (RM3/1 antigen) [18
], and the chemokine AMAC-1 [19
] are the most universal markers to characterize the alternative pathway of activation thus far. So far, molecular characterization of aaM and caM has been carried out mainly using differentially activated macrophages obtained by in vitro steering of human peripheral blood monocytes. However, the in vivo environments in which macrophages develop are far more complex than the environments generated in vitro. Hence, the differential gene-expression data obtained from in vivo-elicited aaM and caM may be more physiologically relevant than those obtained from in vitro-induced macrophages. Moreover, in vivo murine models can be used to study the mechanisms underlying the functional properties of different macrophage populations and their differential activation in ways that would not be conceivable in humans. However, molecular markers for the identification of different macrophage populations in mice are scarce, and so far, discrimination between murine caM and aaM has been based mainly on differential arginine metabolism via iNOS and arginase [5
]. Finally, further characterization of the molecular repertoire of differentially activated macrophages is a prerequisite for a better understanding of the mode of action and differential activation of macrophages, which in turn, may open new avenues toward the development of novel diagnostic and therapeutic approaches. Therefore, using suppression subtractive hybridization (SSH) [20
], we have focused on the identification of genes that are expressed differentially in aaM versus caM in an experimental model of murine trypanosomosis that we have described recently [21
, 22
]. In this model, correlating with a switch from a type I cytokine environment in the early stage of infection to a type II cytokine environment in the late and chronic phases, macrophages from early stage-infected mice are caM, and those from the late and chronic stages of infection are aaM [21
, 22
]. Therefore, this infection model provides a tool for gene-expression profiling of in vivo-elicited caM and aaM.
The results presented in this study demonstrate that the expression of two recently identified genes, FIZZ1 [23
, 24
] and Ym1 [25
, 26
], is induced strongly in aaM as compared with caM.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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-deficient (IL-4R-/-) [28
] BALB/c mice were inoculated intraperitoneally (i.p.) with 2 x 103 phospholipase C-deficient mutant (PLC-/-) Trypanosoma brucei brucei [29
].
Preparation of macrophage populations
Peritoneal exudate cells (PEC) and/or spleen cells (SPC) were collected in the early (2 weeks post-infection), late (5 weeks post-infection), or chronic (4–5 months post-infection) stages of infection. The inoculations were timed so that at the time of PEC/SPC harvest, the mice at different stages of infection were age-matched. All cell cultures were performed in RPMI-1640 medium, supplemented with 10% heat-inactivated fetal calf serum, 5 x 10-5 M 2-mercaptoethanol, 2 mM L-glutamine, 100 U/mL penicillin, 100 µg/mL streptomycin, and 0.1 mM nonessential amino acids (all from Gibco-BRL, Grand Island, NY). To obtain adherent cells, 2 x 107 PEC or 108 SPC were dispensed in a 10-cm tissue-culture dish (Falcon, Becton Dickinson Biosciences, Bedford, MA) and incubated at 37°C for 2–3 h in a humidified incubator containing 5% CO2. Nonadherent cells and contaminating parasites were then washed away with RPMI 1640, prewarmed at 37°C. The status of macrophage activation was determined by measuring NO production and arginase activity of adherent PEC/SPC as described [21
].
For in vitro stimulation, the adherent population of PEC from naive BALB/c mice or BALB/c mice injected i.p. with 3 mL thioglycollate broth (BioMérieux, Marcy l’ Etoile, France) 4 days prior to collection was cultured in the presence of the indicated stimuli for 24 h. The stimuli were used at the following final concentrations: 5 ng/mL IL-13 (R&D Systems, Minneapolis, MN), 100 U/mL IL-4 (Pharmingen, San Diego, CA), 100 U/mL IFN- (Pharmingen), and 100 ng/mL LPS (from Escherichia coli serotype 055:B5; Sigma Chemical Co., St. Louis, MO).
The purity of the macrophage populations was checked via cytofluorimetric analysis, using fluorescein isothiocyanate-conjugated anti-CD11b (Pharmingen) and phycoerythrin-conjugated anti-F4/80 (Serotec, Oxford, UK). Stained cells were analyzed on a FACSVantage SE flow cytometer with CELLQuest analysis software (Becton Dickinson, Sunnyvale, CA). In all cases, the adherent PEC contained 80–90% macrophages.
General molecular techniques
Unless otherwise noted, nucleic acids were handled according to standard protocols [30
]. Total RNA was prepared using Trizol reagent (Gibco-BRL) or RNeasy midi-kit (Qiagen, Chatsworth, CA), as recommended by the suppliers. mRNA was isolated using the Oligotex mRNA midi-kit (Qiagen) following the manufacturer’s instructions. Nucleic-acid homology searches were performed using the FASTA program [31
].
Generation of a subtracted cDNA library
A subtracted cDNA repertoire was generated by SSH [20
] using the PCR (polymerase chain reaction)-Select cDNA subtraction kit (Clontech, Palo Alto, CA). cDNA from adherent PEC from early stage PLC-/- T. b. brucei-infected F1 mice was used as driver. The tester was cDNA from adherent PEC from chronic-stage PLC-/- T. b. brucei-infected animals. The subtracted cDNA repertoire was amplified by PCR according to the manufacturers of the PCR-Select cDNA subtraction kit (Clontech). The resulting PCR products were cloned into the T/A cloning vector pCR2.1 and transferred into E. coli strain TOP10F' (both from Invitrogen, Carlsbad, CA).
Semi-quantitative reverse transcriptase (RT)-PCR
Total RNA (1 µg) was reverse-transcribed using oligo(dT) and Superscript II RT (Gibco-BRL), following the manufacturer’s recommendations. Each PCR cycle consisted of 1 min denaturation at 94°C, 45 s annealing at 55°C, and 1 min extension at 72°C. The PCR primers were FIZZ1 sense (5'-TCCCAGTGAATACTGATGAGA-3'); FIZZ1 antisense (5'-CCACTCTGGATCTCCCAAGA-3'); Ym1 sense (5'-GGGCATACCTTTATCCTGAG-3'); Ym1 antisense (5'-CCACTGAAGTCATCCATGTC-3'); ß-actin sense (5'-ACACTGTGCCCATCTACGAG-3'); and ß-actin antisense (5'-TCAACGTCACACTTCATGATG-3'). The amplicon sizes were 213, 304, and 381 bp for FIZZ1, Ym1, and ß-actin, respectively. The amount of template cDNA and the number of PCR cycles were optimized so that the analysis of PCR products could be carried out within the linear phase of amplification. ß-Actin was used as control to ensure that the observed differences in the expression levels of each gene in different cells were not a result of differences in the amount of template cDNA. The results of the PCR analyses were confirmed in at least three independent experiments.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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and aaM, respectively [21
]. A subtracted cDNA repertoire, putatively enriched for genes up-regulated in aaM, was generated by the SSH method using adherent PEC from early- and chronic-stage PLC-/- T. b. brucei-infected F1 mice. Agarose-gel electrophoresis revealed that the subtracted cDNA repertoire was enriched for three distinct bands. The estimated molecular weights of these bands were 300, 400, and 600 bp (Fig. 1
). A library was generated using the above subtracted cDNA repertoire. Twenty-nine clones were picked randomly and sequenced. A nucleic-acid homology search revealed that out of 29 clones, 1 clone contained a 616-bp fragment of FIZZ1 (RELM), and 11 clones represented Ym1. The inserts of seven and three clones representing Ym1 were about 400 and 300 bp, respectively. The sizes of the inserts of the clones representing FIZZ1 and Ym1, and in particular, the high redundancy of the clones harboring Ym1 gene fragments suggested that the three distinct bands in subtracted cDNA represent FIZZ1 and Ym1 genes. Therefore, in this study, we focused further on the analysis of the expression patterns of these two genes in differentially activated macrophages obtained from PLC-/- T. b. brucei-infected mice or by in vitro steering.
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and aaM, semi-quantitative RT-PCR was performed on RNA from adherent PEC from noninfected (PEC-N), early (PEC-E), and chronic-stage (PEC-C) PLC-/- T. b. brucei-infected F1 mice. These experiments revealed that as compared with PEC-N, aaM (PEC-C) were associated with a strong induction of FIZZ1 and Ym1 (Fig. 2A
). In contrast, FIZZ1 and Ym1 expression was low-to-undetectable in PEC-E (caM; Fig. 2A
). Moreover, as shown in Figure 2B
, differential expression of FIZZ1 and Ym1 in aaM versus caM is not restricted to peritoneal macrophages but is also manifested by adherent cells obtained from the spleens of early- and chronic-stage PLC-/- T. b. brucei-infected F1 mice. Although in noninfected animals, the basal levels of FIZZ1 and Ym1 expression in splenic macrophages seem different from those in peritoneal macrophages (Fig. 2A
and 2B)
, the enhanced expression of FIZZ1 and Ym1 in aaM as compared with caM is indeed independent of the organ sources from which the macrophages are obtained.
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and aaM obtained by in vitro steering of adherent PEC from noninfected BALB/c mice with type I and type II cytokines, respectively. In these experiments, we used resident PEC or PEC from animals inoculated with thioglycollate.
Based on NO production and arginase activity, IL-4-treated, adherent, resident PEC were confirmed to be activated alternatively, whereas treatment with IFN- or LPS resulted in classical activation (Fig. 3A
and B
).
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or LPS (Fig. 3C)
. Simultaneous addition of IFN- antagonized the effect of IL-4 on the expression of FIZZ1 and Ym1 (Fig. 3C)
. In vitro steering of thioglycollate-elicited peritoneal macrophages with IL-4 resulted in alternative activation (Fig. 3D
and 3E)
and induction of FIZZ1 and Ym1 expression (Fig. 3F)
. Similar results were obtained using IL-13 (Fig. 3D
3E
3F)
. In contrast, FIZZ1 and Ym1 expression remained low-to-undetectable upon classical activation of thioglycollate-elicited macrophages by IFN- or LPS (Fig. 3D
3E
3F)
.
Collectively, these results demonstrate that the cytokine environment influences the expression of FIZZ1 and Ym1. Moreover, the above experiments reveal that the expression patterns of FIZZ1 and Ym1 in in vitro-elicited caM and aaM are similar to those in caM and aaM elicited in vivo during PLC-/- T. b. brucei infection.
In vivo induction of FIZZ1 and Ym1 in macrophages from late-stage PLC-/- T. b. brucei-infected mice depends on IL-4
Because IL-4 induces FIZZ1 and Ym1 expression in macrophages in vitro, subsequently, we assessed the role of IL-4 in the in vivo induction of FIZZ1 and Ym1. The expression of FIZZ1 and Ym1 was evaluated in adherent PEC from late-stage (PEC-L) PLC-/- T. b. brucei-infected WT, IL-4-/-, and IL-4R-/- BALB/c mice. In contrast to PEC-L from WT mice, PEC-L from IL-4-/- and IL-4R-/- mice showed no detectable levels of FIZZ1 and Ym1 expression (Fig. 4
). Hence, the in vivo induction of FIZZ1 and Ym1 in macrophages during late-stage PLC-/- T. b. brucei infection is clearly IL-4-dependent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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versus caM elicited during PLC-/- T. b. brucei infection. Our approach yielded a subtracted cDNA repertoire from which the expression patterns of two genes, FIZZ1 and Ym1, were studied further.
FIZZ1 (found in the inflammatory zone), also referred to as RELM, is a resistin-like, secreted protein [23
, 24
]. During allergic, pulmonary inflammation, it is up-regulated markedly in alveolar-epithelial cells and type II alveolar pneumocytes [23
]. Although it cannot be excluded that FIZZ1 contributes to inflammation, the finding that it antagonizes the effect of nerve-growth factor suggests that FIZZ1 may rather be an anti-inflammatory molecule [23
, 32
33
34
].
Ym1 is a chitinase-like, secretory lectin that forms crystals within alveolar spaces and within the cytoplasm of alveolar macrophages and multinucleate giant cells in the lungs of mice exhibiting hyperactivity of alveolar macrophages [25 ]. Because of the association of intracellular and extracellular Ym1 crystals with epithelial damage, Guo et al. [25 ] suggest that Ym1 may contribute to lung inflammation. In contrast, others have suggested anti-inflammatory properties for Ym1 based on its binding specificity. Ym1 binds to heparin and saccharides with a free amino group such as GlcN and GalN [26 , 35 ]. Because of the similarity between the binding specificities of Ym1 and homing receptors of leukocytes, it has been suggested that Ym1 may control leukocyte trafficking by competing with leukocytes for binding sites on local extracellular matrix, and subsequently, this may result in down-regulation of inflammation [26 ]. Although Ym1 was described originally as an eosinophil-chemotactic factor [36 ], a recent study contradicts this finding [26 ]. In accordance, our histological studies did not reveal significant differences between the eosinophil counts of the PEC from early- and chronic-stage PLC-/- T. b. brucei-infected mice (unpublished results), suggesting that in our model, Ym1 is not acting as an eosinophil attractant.
We demonstrated that aaM are associated with strong induction of FIZZ1 and Ym1 expression for peritoneal and splenic macrophages generated during chronic-stage PLC-/- T. b. brucei infection, as well as for aaM induced in vitro via steering with the type II cytokines IL-4 and IL-13. The basal levels of FIZZ1 and Ym1 in peritoneal and splenic macrophages seem to be different, possibly reflecting differences in the local microenvironment, such as differences in cytokine and chemokine levels and the type and frequency of different cells. However, in all the conditions tested, there was a consistent increase in FIZZ1 and Ym1 expression in aaM compared with caM. Hence, FIZZ1 and Ym1 seem to be reliable markers for aaM. The observation that IFN- counteracts IL-4-mediated up-regulation of FIZZ1 and Ym1 in vitro suggests that in vivo, a type I cytokine environment may contribute to maintaining low FIZZ1 and Ym1 expression levels in caM. Type I cytokines may have a direct effect(s) on FIZZ1 and Ym1 expression or may act indirectly on these genes by preventing the generation of aaM. Using IL-4-deficient mice, we demonstrated that the expression of FIZZ1 and Ym1 in macrophages from late-stage PLC-/- T. b. brucei-infected mice depends on IL-4. Because late-stage PLC-/- T. b. brucei-infected, IL-4-deficient mice do not express detectable levels of IL-13 (unpublished results), our experiments do not allow us to address whether in the absence of IL-4, IL-13 can induce the expression of FIZZ1 and Ym1 in vivo. Our results, describing the up-regulation of FIZZ1 and Ym1 in aaM, are in agreement with other studies showing a correlation between a type II cytokine environment and high expression of FIZZ1 and/or Ym1 in peritoneal macrophages from mice infected with Brugia malayi (ref. [9
]; and J. Allen, personal communication) or Trichinella spiralis [26
]. Importantly, in contrast to the B. malayi and T. spiralis infection models that induce only aaM, different macrophage populations arise during PLC-/- T. b. brucei infection, therefore allowing us to compare the expression profiles of aaM and caM.
Because aaM are associated with FIZZ1 and Ym1 expression, FIZZ1 and Ym1 may be effector molecules implicated in the functional properties of aaM. Indeed, as compared with mice infected with WT T. b. brucei, PLC-/- T. b. brucei-infected animals produce reduced amounts of inflammatory mediators [12
, 22
]. Hence, a role for FIZZ1 and Ym1 in down-regulating inflammation during PLC-/- T. b. brucei infection cannot be excluded. However, the function of FIZZ1 and Ym1 in general and in aaM in particular remains an open question that is beyond the scope of this paper.
In conclusion, the results of this study demonstrate that PLC-/- T. b. brucei infection provides a physiologically relevant model for the identification of genes that are expressed differentially in aaM versus caM. FIZZ1 and Ym1 are the first two such genes that we identified using this model. We demonstrated that aaM are, in an IL-4-dependent manner, associated with high levels of FIZZ1 and Ym1 expression. Because of their differential expression in aaM versus caM, FIZZ1 and Ym1 constitute useful markers for the identification of aaM. Such identification is a critical step in addressing the contribution and effector mechanisms of aaM in the various biological processes with which they are associated, including immune suppression and immune deviation during parasitic infection [8
, 11
], cancer [37
, 38
], pulmonary inflammation [25
], and wound healing [7
].
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Note added in proof |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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. Moreover, the authors described the Ym2 sequence, which shows 92% identity with Ym1. The primers used in our study do not discriminate between Ym1 and Ym2, and therefore, we do not exclude the possibility that Ym2 is also up-regulated in aaM.
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ACKNOWLEDGEMENTS |
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Received August 25, 2001; revised November 2, 2001; accepted December 12, 2001.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONNote added in proofREFERENCES |
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, a novel structural homologue of macrophage inflammatory protein-1 with a Th2-associated expression pattern J. Immunol. 160,1411-1418This article has been cited by other articles:
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L. Brys, A. Beschin, G. Raes, G. H. Ghassabeh, W. Noel, J. Brandt, F. Brombacher, and P. D. Baetselier Reactive Oxygen Species and 12/15-Lipoxygenase Contribute to the Antiproliferative Capacity of Alternatively Activated Myeloid Cells Elicited during Helminth Infection J. Immunol., May 15, 2005; 174(10): 6095 - 6104. [Abstract] [Full Text] [PDF]
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