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Divisions of
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Allergy and Immunology and
Pediatric Informatics, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and signaling through STAT6 (12, 13). Mice with targeted deletion of IL-4, IL-13, or STAT6 develop attenuation of certain features of asthma, including inflammatory cell infiltrates and airway hyperresponsiveness (AHR)3 (14, 15). Although these studies have provided the rationale for the development of multiple therapeutic agents that interfere with specific inflammatory pathways (16, 17, 18, 19), the development of the asthma phenotype is likely to be related to the complex interplay of a large number of genes. In this study, we aimed to gain critical insight into the spectrum of genes involved in the pathogenesis of experimental asthma, to define the genetic variability between two "phenotypically similar" asthmatic states, and to use transcript profiling to further uncover the importance of STAT6 pathways in the pathogenesis of disease. |
Materials and Methods |
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BALB/c mice (National Cancer Institute, Frederick, MD) and STAT6-deficient mice (20) (BALB/c background, The Jackson Laboratory, Bar Harbor, ME) were housed under specific pathogen-free conditions. Asthma models were induced by two i.p. injections of OVA and aluminum hydroxide, followed by two OVA or saline intranasal challenges 3 days apart, as previously described (21). Mice were sacrificed 3 or 18 h following the first or second allergen challenge. Aspergillus fumigatus Ag-associated asthma was induced by exposing mice intranasally three times a week for 3 wk as described elsewhere (22, 23, 24). Mice were sacrificed 18 h following the last challenge. In some experiments, bronchoalveolar lavage fluid (BALF) was collected and infiltrating cells differentiated. However, in experiments in which RNA was collected for microarray analysis, BALF was not performed.
Preparation of RNA and microarray hybridization
RNA was extracted using the TRIzol reagent as per the manufacturer’s instructions. Following TRIzol purification, RNA was repurified with phenol-chloroform extraction and ethanol precipitation. Microarray hybridization was performed by the Affymetrix GeneChip Core facility at Children’s Hospital Medical Center using the murine U74Av2 GeneChip (Affymetrix, Santa Clara, CA) as previously reported (21). This analysis was performed with one mouse per chip (n 
3 for each allergen challenge condition and n 2 for each saline challenge condition). A further description of the methodology according to the Minimum Information About a Microarray Experiment guidelines (available at www.mged.org/Workgroups/MIAME/miame.html) is provided in supplementary information.
Microarray data analysis
From data image files, gene transcript levels were determined using algorithms in the Microarray Analysis Suite version 5 software (Affymetrix). Global scaling was performed to compare genes from chip to chip, as previously reported (21). Differences between saline- and OVA-treated mice were also determined using the GeneSpring software (Silicon Genetics, Redwood City, CA). Data for each allergen challenge time point was normalized to the average of the saline-treated mice. Gene lists were created as previously reported (21). Student’s t test with the multiple testing correction of Benjamini and Hochberg false discovery rate was used. Functional classifications were based on the Gene Ontology classification (25) obtained through the NetAffx server (available at www.netaffx.com) and public information in GenBank. Supplementary Tables I4 through 6 contain the gene lists presented in this article and analyzed as described here. Raw data used for supplementary Tables III (OVA) and 4 (Aspergillus) are the same as the one used for supplementary Tables II and III in our previous publication (21). However, analysis for the current article was performed in the updated Microarray Suite, version 5. Several genes are represented by more than one probe set on the chip; thus, the actual number of genes on a certain list may be lower due to duplication.
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The cDNA probes, generated by PCR or from commercially available vectors (American Type Culture Collection, Manassas, VA) were sequence confirmed, radiolabeled with 32P, and hybridized as previously reported (24, 26, 27).
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Results |
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We were interested in reproducibly and accurately identifying genes that were differentially expressed in a well-established model of asthma. Thus, mice were sensitized and challenged using the OVA model (Fig. 1A). We first analyzed global gene expression profiles at an early time point (3 h) after the first allergen encounter. Indeed, only 36 genes were induced by early encounter with allergen (Fig. 1B, Table I, and supplementary Table I). Genes encoding for molecules involved in early recognition of foreign pathogens were induced, including CD14 and a C-type lectin (28). Genes involved in initiating innate responses were induced, including CD83 (a dendritic cell activation marker), members of the IL-1 family (IL-1, IL-1
, and IL-1R antagonist), numerous chemoattractants including chemokines active on neutrophils (CXC chemokine ligand (CXCL) 1, CXCL2), and myeloid-related proteins (MRP) 8 and MRP 14 (29) (Fig. 1, C and D, and data not shown). Consistent with myeloid cell recruitment, the gene for G-CSF receptor was elevated in the early response. Interestingly, genes not known to be expressed in the lung were among the early allergen-induced genes. For example, there was ectopic expression of several members of the schlafen family of growth-regulating genes, previously shown to be expressed only in the thymus (30).
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; indeed, a member of this family of molecules (ADAM-33) has recently been identified as a human asthma gene (33). Trefoil factor 2 and Gob5, also among the genes induced 18 h after the initial challenge, have a role in mucus production (34, 35). This indicates that the genetic program for chronic processes, such as mucus production and airway remodeling, is already underway 18 h after the first allergen challenge. Consistent with this, unlike the acute time point, there was not a unique "genetic signature" compared with genes induced 18 h after two allergen challenges. In fact, most genes that were induced 18 h after the first allergen challenge were further increased following the second challenge. Additionally, similar to early genes, there was apparent ectopic expression of genes not previously shown to be expressed in the lung such as intelectin (an intestinal lectin) and trefoil factor 2 (an intestinal gene) (36, 37, 38). We next focused our attention on characterizing the genes induced following the second allergen challenge. A different set of chemokines (e.g., eotaxin (CC chemokine ligand (CCL11), macrophage chemoattractant protein-2 (CCL8)) was induced following second allergen challenge (supplementary Table III). Consistent with the target cells of the induced chemokines, the genes encoding for macrophage-associated markers were induced (CCR5, CCR2, and F4/80). In addition, specific genes involved in cytoskeleton rearrangement, such as scinderin, were induced. Genes regulating cell proliferation such as cyclin B1 and B2, Ki-67, topoisomerase II, and spermidine synthase were elevated. A series of relevant transcription factors were induced such as the proinflammatory NF of activated T cells (NFAT)c. Additionally, the late asthma gene set encoded for a variety of serine proteases (including complement proteins (C1q, Properdin) and coagulation factors VII and X). Indeed, fibrin deposition and complement activation in the asthmatic lung have been reported (39, 40, 41, 42). In addition, the late asthma gene set contained numerous protease inhibitors implicated in tissue repair such as the cathepsin genes. Additionally, a series of small proline-rich (SPRR) proteins involved in squamous cell differentiation and remodeling (43, 44) were induced. Table I provides an extensive summary of dynamically regulated genes and verification of representative early and late genes by Northern blot analysis is shown in Fig. 1D.
Over the course of our studies, we have used Northern blot analysis to examine expression of a series of genes identified by microarray analysis. In particular, we have examined 30 of the putatively OVA-induced genes, and all were shown to be increased by Northern blot analysis. Those genes included SPRR2, Kreisler, arginase I and II, granzyme B, ADAM-8, heme oxygenase, acidic chitinase, trefoil factor 2, RELM-, matrix metalloprotease 12, TDAG8, 12/15-lipoxygenase, cationic amino acid transporter 2, chemokines CCL2, CCL5, CCL6, CCL7, CCL8, CCL9, CCL11, CCL12, CXCL1, CXCL5, CXCL9, CXCL10, CXCL12, and chemokine receptors CCR1, CCR2, and CCR5. Importantly, at least half of these genes were unexpected (i.e., they were not previously known to be expressed in the lung or induced by allergen challenge). Collectively, these results indicate a very low rate of false positives in the allergen-induced gene lists.
To systematically analyze genes induced by allergen challenge, we assigned them into functional categories (Table II). Additionally, we identified and classified 62 genes that were decreased by at least 2-fold compared with saline-challenged mice. Immune-related genes were predominantly in the increased group (39%) compared with the decreased group (2%). In contrast, genes involved in development and homeostasis composed the majority of decreased genes (67%), while only comprising 24% of the increased genes.
Since many of the genes induced were related to the immune response, we hypothesized that distinct chromosomal loci (rich for immune-related gene families) were induced by allergen challenge. Thus, we analyzed the chromosomal location of genes induced following two allergen challenges (Fig. 1E). Initially, we searched for clusters (more than five probe sets per 2 cM) and five were identified. For instance, on chromosome 6, transcripts for the Ig L chain 
were overrepresented among the increased genes. Similarly, on chromosomes 12 and 17 there were several transcripts from the Ig H chain locus and the major histocompatibility locus (H2), respectively. Finally, both the CC and CXC chemokine clusters (on chromosomes 11 and 5, respectively) were heavily represented. When the total number of genes induced by allergen challenge on a particular chromosome was normalized for the number of genes present on that chromosome, we found that the majority of chromosomes contained a comparable amount of genes induced by allergen challenge. Fisher’s test for overrepresentation of increased genes on individual chromosomes revealed that only chromosome 6 had a significant increase (p = 0.03).
Comparison of OVA and A. fumigatus-induced experimental asthma
We were next interested in comparing global transcript profiles in two independent models of asthma. We analyzed experimental asthma induced by A. fumigatus Ags because this model involves a unique mucosal sensitization route (intranasal) compared with the OVA model (45) and because A. fumigatus is a ubiquitous and common aeroallergen. Importantly, both asthma models have similar phenotypic and histological features including Th2-associated eosinophilic inflammation, mucus production, collagen deposition, and AHR (21, 22, 23, 41, 42, 43, 44, 45, 46, 47). Eighteen hours after nine doses of intranasal A. fumigatus allergen challenge, lung RNA was subjected to the same microarray and data processing analyses as those performed after OVA challenges. Compared with mice challenged with intranasal saline, A. fumigatus-challenged mice had 387 genes induced (Fig. 2A and supplementary Table IV). This was compared with the 436 genes that were induced following OVA challenges, irrespective of the time and dose. The majority (56% of OVA and 63% of Aspergillus) of the induced transcripts overlapped between the two experimental asthma models. However, 194 (44% of the 436 genes increased following OVA challenges) and 145 (37% of genes increased by Aspergillus) genes were unique for the OVA and A. fumigatus models, respectively. The genes for several cell-specific markers including granzymes A and B (normally present in cytotoxic cells and NK cells) (48, 49, 50) and mouse mast cell proteases 2 and were only seen in the OVA model (Fig. 2A). Northern blot analysis confirmed specific granzyme B mRNA accumulation in the OVA model (Fig. 2, B and C). In contrast, in A. fumigatus-induced asthma, the genes that were specifically up-regulated included the genes for coagulation factor III, complement component I, and the extracellular adhesion molecule laminin thought to be involved in remodeling processes. Northern blot analysis confirmed Aspergillus-specific expression of CIDE-B (cell death-inducing DFF45-like effector B), a member of a novel family of cell death activators that has been demonstrated to be expressed in hemopoietic organs (51). Thus, despite roughly similar asthma phenotypes, two independent asthma models were characterized by a large number of uniquely dysregulated genes.
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Role of STAT6 in experimental asthma
A central question in the asthma field is to elucidate the role of the IL-4R/STAT6 pathway since these molecules seem to be essential for many of the hallmark features of asthma. We initially hypothesized that the vast majority of asthma signature genes would be STAT6 dependent. To test this hypothesis, we subjected STAT6-deficient mice to the OVA protocol (with two allergen or saline challenges). Lung RNA was analyzed by microarray analysis and compared with wild-type mice subjected to the same protocol. Consistent with our hypothesis, only 60 genes increased in OVA compared with saline-challenged STAT6-deficient mice (Fig. 3A and supplementary Table V). This is in sharp contrast to 414 genes induced by allergen challenge in wild-type mice. Overlap of the two groups of genes is depicted in Fig. 3A. This analysis established 373 STAT6-dependent genes (i.e., they were not increased in STAT6-deficient OVA-challenged compared with saline-challenged mice). In contrast, there were 41 STAT6-independent genes (i.e., they were increased in STAT6-deficient OVA-challenged compared with saline-challenged mice). Examples of genes identified in the STAT6-dependent group include eotaxin-1 and arginase I, consistent with previous studies (21, 24), and SPRR2A (Fig. 3, B and C). Additionally, granzyme B and mouse mast cell protease 8, previously mentioned as OVA-specific genes, were also STAT6 dependent. Thus, it appears that genes from multiple source cells, including epithelial, NK, CTL, and mast cells, are dependent on STAT6-mediated transcription. Among the STAT6-independent genes, we observed several chemokines, mostly of the CXCL family, macrophage scavenger receptor and a C-type lectin. The STAT6-independent chemokines included CXCL10 (IFN-inducible protein 10, Fig. 3, B and C), a CXCR3 ligand that exhibits an inhibitory effect on CCR3-mediated eosinophil functions (53). Induction of CXCR3 ligands in allergic asthma has been demonstrated to be IFN-
dependent (54), which is consistent with our finding that STAT6 is not required. Collectively, our data indicate that the majority of OVA-induced genes are dependent on STAT6, consistent with the observed decrease in eosinophilic infiltration in the BALF (Fig. 3D), peribronchial inflammation, mucus production, and AHR (14, 55) in STAT6-deficient mice. However, a smaller portion of genes is STAT6 independent, suggesting alternative cytokine signaling events, such as IFN-, in experimental asthma. Notably, the sustained allergen-induced BALF neutrophilia (Fig. 3D) is likely explained by these STAT6-independent genes, at least in part.
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Discussion |
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4.7% of the tested genome indicates that a vast number of gene products, many of which were not known to be expressed in the lung, contribute to disease pathogenesis at least to some degree. Although there are particular "hot spots" for asthma gene transcription (primarily chemokine, H2, and Ig loci), the allergen-induced genes span the entire genome. Functional classification identified a predominance of immunity genes, but also a surprisingly large number of genes involved in development and homeostasis and significant numbers of genes involved in diverse processes including transcription, cell cycle regulation, and signal transduction. Initially, we characterized the early time points following allergen challenge and demonstrated that genes involved in early recognition of foreign pathogens and initiating immune responses were predominant. This is consistent with innate immune responses active early in the process. Conversely, at later time points, there was a preponderance of genes involved in adaptive immunity as well as pathophysiological processes associated with chronic asthma, such as fibrosis. The finding that similar asthma states in mice are composed of a large number of nonoverlapping dysregulated genes indicates that the genetic programs are dependent upon the mode of disease induction, at least in part. Our experimental induction protocols utilized largely different experimental regimens. Indeed, diverse induction modes (with variable involvement of natural adjuvants such as endotoxin or diesel exhaust particles) are likely to be responsible for human asthma. In our study, we used two independent protocols. Although Aspergillus is a mixture of multiple proteins, including ones with protease activity, the OVA preparation is more uniform. Furthermore, differential contamination with LPS or other pattern recognition molecules may account for some of the gene induction activity. Indeed, recently low levels of LPS present in OVA have been shown to effect induction of allergic airway inflammation (57). Thus, contaminating LPS in the OVA or Aspergillus preparations could have effects on the observed gene inductions. However, our preparations of OVA and Aspergillus have no detectable LPS as measured by the Limulus assay (limit of detection = 2 pg/ml); additionally, we have observed that treatment of the Ag preparations with an endotoxin removal column (polymixin B) had no impact on the ability of these Ag preparations to induce experimental asthma (data not shown). Additionally, the route of sensitization (mucosal for Aspergillus and systemic for OVA) is different between the two protocols. Finally, the timing of sensitization and challenge also differs between the two models. Notably, despite these differences, the phenotype observed in the lungs of mice is similar (Refs. 21, 22, 23 ,46 and 47 and Figs. 3 and 4). Taken together, our analysis has identified genes common to two independent protocols consistent with similar phenotypes observed as well as genes unique to a specific protocol, suggesting independent mechanisms can lead to allergic airway inflammation, at least in part. The dissection of global transcript profiles provides a valuable opportunity to identify new pathways. For example, the identification of the involvement of the SPRR proteins and members of the chitinase family represents novel pathways that are likely involved in processes relevant to airway remodeling and inflammation. Proteins of the SPRR family appear to be involved in differentiation of epithelial cells. Although the majority of studies have focused on the role of SPRR proteins in the epithelium of skin and upper gastrointestinal tract, we find induction of SPRR2 in the bronchial epithelium (by in situ hybridization, data not shown). Similarly, we demonstrate that several members of the chitinase family are significantly induced during experimental asthma. Since chitin is a common element in parasites and fungi, but does not occur in mammalian tissues, chitinases may serve an antimicrobial role or participate in the removal of chitin-containing Ags. The related chitinases, gp39 and gp38K, have been demonstrated to play a role in tissue remodeling (58, 59); thus, while chitinases in asthma may be induced as part of the innate mechanism to clear chitin, these enzyme are likely to be contributing in disease pathogenesis. It has not escaped our attention that the asthma signature genes include products of alternatively activated macrophages (i.e., arginase I, 15-lipoxygenase, and YM-1). Although alternatively activated macrophages have been primarily classified by the expression of these IL-4/IL-13-induced genes in vitro, our results draw attention to the participation of alternatively activated macrophages in asthmatic responses in vivo. Additionally, we observed induction of MRP 8 and MRP 14, myeloid chemoattractants of the calcium S100 family, that have not been previously implicated in allergic or asthmatic responses (29).
We have determined that a large portion of the asthma signature genome is STAT6 independent. This is an unexpected result in view of the central requirement of IL-4/IL-13/STAT6 signaling in allergic airway inflammation (14, 55). However, these results are consistent with recent studies demonstrating that certain aspects of asthma, specifically in the chronic phase of the disease, are relatively STAT6 independent (34, 60, 61). Interestingly, a subset of genes is STAT6 dependent in the OVA model and STAT6 independent in the Aspergillus model. Although the mechanism of this finding warrants future investigations, it is interesting to speculate on several possibilities. First, it remains possible that specific genes are produced by different cell types in the two models; each cell type may have distinct STAT6 dependence due to the absence or presence of STAT6 or IL-4R. Second, the Aspergillus model represents a more chronic model compared with the OVA model, and there may thus be distinct regulation pathways (at different relative time points), as we have observed with TFF2 (34). Third, certain genes may be regulated by cytokines and transcription factors that are Th2 associated (STAT6), but not Th2 restricted (e.g., NF-B); thus, there may be alternative signaling pathways induced by Aspergillus in the absence of STAT6. Although we have not directly addressed the role of IL-4 and IL-13, our results suggest that asthma can bypass the classic IL-4/IL-13/STAT6 pathway. It is notable that in the absence of STAT6, a new asthma program is elicited, suggesting that certain elements of airway inflammation and disease may be sustained or exacerbated by blockade of STAT6. Identification of STAT6-independent genes and pathways will facilitate taking new approaches in the scientific analysis of the asthma problem and rational design of future therapeutics. Previous studies have determined that Th2 responses can occur independent of STAT6 in the absence of the Bcl6 or CTLA4 molecules (62, 63). Thus, the observed STAT6-independent transcription may arise from suppression of Bcl6-associated transcription and/or by strong T cell costimulation. These pathways will need to be considered for rational design of future asthma therapies. Although we are at the early stages of transcript profile analysis of allergic airway inflammation, these findings have important clinical and therapeutic ramifications.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marc E. Rothenberg, Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E-mail address: Rothenberg{at}cchmc.org
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; BALF, bronchoalveolar lavage fluid; CXCL, CXC chemokine ligand; CCL, CC chemokine ligand; MRP, myeloid-related protein; ADAM, a disintegrin and metalloprotease; SPRR, small, proline rich.
4 The on-line version of this article contains supplemental material.
Received for publication August 6, 2003. Accepted for publication November 17, 2003.
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N. Zimmermann, M. P. Doepker, D. P. Witte, K. F. Stringer, P. C. Fulkerson, S. M. Pope, E. B. Brandt, A. Mishra, N. E. King, N. M. Nikolaidis, et al. Expression and Regulation of Small Proline-Rich Protein 2 in Allergic Inflammation Am. J. Respir. Cell Mol. Biol., May 1, 2005; 32(5): 428 - 435. [Abstract] [Full Text] [PDF]
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H. Takatori, H. Nakajima, K. Hirose, S.-i. Kagami, T. Tamachi, A. Suto, K. Suzuki, Y. Saito, and I. Iwamoto Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation J. Immunol., March 15, 2005; 174(6): 3734 - 3740. [Abstract] [Full Text] [PDF]
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P. C. Fulkerson, N. Zimmermann, L. M. Hassman, F. D. Finkelman, and M. E. Rothenberg Pulmonary Chemokine Expression Is Coordinately Regulated by STAT1, STAT6, and IFN-{gamma} J. Immunol., December 15, 2004; 173(12): 7565 - 7574. [Abstract] [Full Text] [PDF]
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 N. E. King, M. E. Rothenberg, and N. Zimmermann Arginine in Asthma and Lung Inflammation J. Nutr., October 1, 2004; 134(10): 2830S - 2836S. [Abstract] [Full Text] [PDF]
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) and allergen (
) challenge is depicted. Error bars represent the SD. The values represent mean ± SD. Raw data used for OVA and Aspergillus are the same as the ones used in our previous publication (
) and allergen (