Gene expression profiling following NRF2 and KEAP1 siRNA knockdown in human lung fibroblasts identifies CCL11/Eotaxin-1 as a novel NRF2 regulated gene
© Fourtounis et al.; licensee BioMed Central Ltd. 2012
Received: 6 August 2012
Accepted: 10 October 2012
Published: 12 October 2012
Oxidative Stress contributes to the pathogenesis of many diseases. The NRF2/KEAP1 axis is a key transcriptional regulator of the anti-oxidant response in cells. Nrf2 knockout mice have implicated this pathway in regulating inflammatory airway diseases such as asthma and COPD. To better understand the role the NRF2 pathway has on respiratory disease we have taken a novel approach to define NRF2 dependent gene expression in a relevant lung system.
Normal human lung fibroblasts were transfected with siRNA specific for NRF2 or KEAP1. Gene expression changes were measured at 30 and 48 hours using a custom Affymetrix Gene array. Changes in Eotaxin-1 gene expression and protein secretion were further measured under various inflammatory conditions with siRNAs and pharmacological tools.
An anti-correlated gene set (inversely regulated by NRF2 and KEAP1 RNAi) that reflects specific NRF2 regulated genes was identified. Gene annotations show that NRF2-mediated oxidative stress response is the most significantly regulated pathway, followed by heme metabolism, metabolism of xenobiotics by Cytochrome P450 and O-glycan biosynthesis. Unexpectedly the key eosinophil chemokine Eotaxin-1/CCL11 was found to be up-regulated when NRF2 was inhibited and down-regulated when KEAP1 was inhibited. This transcriptional regulation leads to modulation of Eotaxin-1 secretion from human lung fibroblasts under basal and inflammatory conditions, and is specific to Eotaxin-1 as NRF2 or KEAP1 knockdown had no effect on the secretion of a set of other chemokines and cytokines. Furthermore, the known NRF2 small molecule activators CDDO and Sulphoraphane can also dose dependently inhibit Eotaxin-1 release from human lung fibroblasts.
These data uncover a previously unknown role for NRF2 in regulating Eotaxin-1 expression and further the mechanistic understanding of this pathway in modulating inflammatory lung disease.
KeywordsAsthma NRF2 KEAP1 Oxidative stress Eotaxin regulation Microarray profiling
Oxidative stress in tissues leads to the generation of reactive oxygen species which can interfere with normal cellular function and homeostasis and can contribute to the pathophysiology of many diseases including cancer, atherosclerosis, ischemia reperfusion injury, neurodegenerative disorders and aging . The lung is highly susceptible to oxidant stress since it is exposed to high amounts of oxygen  and exogenous oxidants found in environmental pollution such as ozone or diesel exhaust particles . As such, markers of oxidative stress are present in the lungs of people with many pathological conditions including asthma [4, 5], COPD  and acute lung injury [7, 8]. There is a large body of evidence from clinical and preclinical studies that this oxidative stress is a key contributor to the disease pathophysiology [9–17] and can modulate responses to pharmacological respiratory therapeutics .
Since oxidative stress can have such detrimental effects to the health of the organism, there has evolved an extensive endogenous intracellular and extracellular anti-oxidant system to maintain redox homeostasis . One of the key regulators of this endogenous anti-oxidant system is the transcription factor nuclear factor (erythroid-derived 2)-like 2 (NFE2L2, NRF2). NRF2 is basic leucine zipper (bZIP) transcription factor that regulates the expression of numerous genes that encode anti-oxidant and detoxifying phase II enzymes through the binding to cis-acting anti-oxidant response elements (AREs) found in the promoters of these genes. Thus, NRF2 acts as the master regulator of the cellular response to oxidant injury . In order to ensure that the anti-oxidant response is appropriately regulated, under conditions of redox homeostasis NRF2 is sequestered in the cytoplasm by binding through its N-terminal Neh2 domain to Kelch-like ECH-associated protein 1 (KEAP1) [20, 21]. KEAP1 also functions as a substrate adaptor for the cullin-dependent E3 ligase and targets NRF2 for ubiquitination and degradation by the 26S proteasome [22, 23]. Several stimuli including oxidants, toxic agents and electrophilic agents can lead to an oxidation of key sulphydryl groups on KEAP1 leading to the release of NRF2 where it can enter the nucleus and activate the anti-oxidant machinery [24, 25]. In support of this, it has been shown that KEAP1 deficiency results in constitutive activation of NRF2 responsive gene expression .
There is significant data suggesting a critical role for NRF2 in preventing lung disease. Studies in COPD patients have shown that NRF2 dependent genes are activated in disease , but that as disease progresses there is a defect in this antioxidant response . In preclinical species, there is increased expression of NRF2 regulated genes in cigarette smoke induced models of COPD  and in allergic lung models  implicating NRF2 as an endogenous regulator of oxidative stress in these models. This critical role has been confirmed in studies using Nrf2 deficient mice. In an allergen-induced model of airway inflammation, loss of Nrf2 has been shown to result in an increase in cellular recruitment to the lung, mucus hypersecretion and airway hyperresponsiveness . Similarly, in cigarette smoke-induced models of COPD, Nrf2 deficiency leads to an increase in inflammation and emphysema [31, 32]. Additionally, Nrf2 deficient mice have also been shown to have increased susceptibility to acute lung injury  and Respiratory Syncytial virus infection . Importantly, treatment of mice with pharmacological agents that can activate NRF2 can lead to the inhibition of cigarette smoke  and allergen induced pathology in the lung . Thus, there is a clear demonstration of the critical role of the endogenous anti-oxidant response and NRF2 in regulating airway disease.
In order to understand the precise mechanisms of the NRF2 induced anti-oxidant response, researchers have largely turned to expression profiling experiments to determine those genes that mediate NRF2 activity in the tissue or model of interest. Most of these studies have utilized Nrf2 deficient mice or pharmacological treatment of various NRF2 activating compounds to define the NRF2 responsive genes [36–41]. These studies have lead to a well established group of NRF2 regulated genes, however, many novel or differentially regulated genes have been identified suggesting that there are species, tissue and model dependent differences in NRF2 regulated gene expression [42–47].
In this study we have taken a novel approach to define NRF2 dependent gene expression in normal primary human lung fibroblasts. These cells were chosen owing to the known role of oxidative stress pathways in fibroblasts , and the known role of fibroblasts to airway remodelling and a source of inflammatory mediators involved in asthma [49–51]. We have utilized siRNA to selectively and robustly knockdown the transcript levels of both NRF2 and KEAP1. Using microarray profiling we have defined a distinct set of anti-regulated genes as well as genes specifically modulated by KEAP1 or NRF2 knockdown. Interestingly, we report the discovery that NRF2 activation by KEAP1 knockdown or by pharmacological activators of NRF2 can specifically inhibit Eotaxin-1/CCL11 expression in human lung fibroblasts independent of several other chemokines further implicating this pathway in asthma pathogenesis.
(A) Nrf2-mediated oxidative stress response genes knock down by NRF2 siRNAs and (B) Wnt/b-catenin signaling genes modulated by KEAP1 siRNAs
A. NRF2-mediated Oxidative Stress Response
NAD(P)H dehydrogenase, quinone 1
thioredoxin reductase 1
heme oxygenase (decycling) 1
microsomal glutathione S-transferase 1
glutamate-cysteine ligase, modifier subunit
ferritin, heavy polypeptide 1
carbonyl reductase 1
epoxide hydrolase 1, microsomal (xenobiotic)
ferritin, light polypeptide
ubiquitin specific peptidase 14 (tRNA-guanine transglycosylase)
glutathione S-transferase M4
glutathione S-transferase M5
mitogen-activated protein kinase 14
glutamate-cysteine ligase, catalytic subunit
superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))
aldo-keto reductase family 7, member A2 (aflatoxin aldehyde reductase)
B. Wnt/β-catenin Signaling
secreted frizzled-related protein 1
dickkopf homolog 2 (Xenopus laevis)
dickkopf homolog 1 (Xenopus laevis)
frizzled homolog 7 (Drosophila)
protein phosphatase 2 (formerly 2A), regulatory subunit B”, alpha
transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47)
SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal)
CD44 molecule (Indian blood group)
dickkopf homolog 3 (Xenopus laevis)
SRY (sex determining region Y)-box 3
transducin-like enhancer of split 1 (E(sp1) homolog, Drosophila)
gap junction protein, alpha 1, 43 kDa
SRY (sex determining region Y)-box 4
wingless-type MMTV integration site family, member 3
siRNA transfection and RNA preparation for microarray
Briefly, endoribonuclease-prepared short interfering RNAs (esiRNA) (KEAP1) or siRNA pools (10 individual siRNAs for each; pool 1: siRNA 1-10, pool 2: siRNA 11-20, pool 3: siRNA 21-30; see Additional file 1) for NRF2 and KEAP1 were incubated with Hiperfect reagent (Qiagen) in basal media (Lonza, # CC-3131) with no serum or antibiotics and allowed to complex for 10 min at room temperature. During this incubation, normal human lung fibroblasts (Lonza, #CC-2512) were plated in T25 flasks (6 × 105 cells/flask) in media containing 2% serum and growth factors but no antibiotics. The complex was then added to the cell suspension of each well (final siRNA pool concentration of 10 nM, 1 nM of each siRNA). Cells were then incubated for 30 hr or 48 hr in a humidified incubator. At the end of the incubation period, the culture medium was removed and the cells were lysed by direct resuspension in Trizol reagent (Invitrogen, CA). Crude total RNA was isolated from Trizol-dissolved samples and purified using the RNAeasy kit (Qiagen) as per the manufacturer’s instructions. RNA concentration was measured using a NanoDrop ND-1000 (NanoDrop Technologies, Wilmington, DE), and RNA integrity was determined with a 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA). Samples displaying a RNA integrity number greater than 8 were used for profiling.
Affymetrix GeneChip experiment
Samples were amplified and labelled using a custom automated version of the RT/IVT protocol and reagents provided by Affymetrix. Hybridization, labelling and scanning were completed following the manufacturer’s recommendations (Affymetrix). For data analysis, we used the mock-transfected sample as the reference to compare with all other time-matched samples to obtain the ratio data. Merck/Affymetrix human custom arrays monitoring 43,737 individual transcripts were used. Raw intensity was normalized using the RMA algorithm. Enrichment for biological processes was performed by comparing each gene signature against the public gene collections Gene Ontology, KEGG, Swissprot and Panther families. Enrichment P values (hypergeometric distribution) were corrected for multiple testing by using Bonferroni correction. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA) (http://www.ingenuity.com/index.html). Overlap of each gene signature with other publicly available gene signatures was performed by using NextBio libraries (NextBio) (http://nextbio.merck.com/c/nextbio.nb).
NRF2 and KEAP1siRNA transfection for Q-PCR and chemokine/cytokine mesurements
Briefly, siRNA pools for NRF2 and KEAP1 were incubated with Hiperfect reagent (Qiagen, # 301705) in basal media (Lonza, # CC-3131) with no serum or antibiotics and allowed to complex for 10min at room temperature. During this incubation, normal human lung fibroblasts (Lonza, #CC-2512) were plated in 24-well or 96-well plates (Costar # 3524, BD Falcon # 353948), at 4×104 or 2×104 cells/well, respectively, with 2% serum but no antibiotics. The complex was then added to the cell suspension for each well (final siRNA pool concentration of 10 nM). Cells were then incubated for 48 hrs in a humidified incubator. After 48 hrs, cells were challenged with 1 ng/ml of human IL-1β (R+D systems # 201-LB-005) or PBS-0.1% BSA control for 18hrs. After 18 hrs challenge, cells were spun down for RNA isolation and supernatants were removed for cytokine and chemokine measurements.
Real time quantitative PCR
Total RNA was isolated using QIAGEN RNeasy mini tubes according to the manufacturer’s animal cell extraction protocol (QIAGEN # 74106) which included the DNase step (QIAGEN # 79254). All TAQMAN probes were purchased from Applied Biosystems. Reverse transcription was performed in 100 μl of reaction solution using the following reagents per condition (Applied Biosystems # N808-234): 10 μl of 10X reverse transcription buffer, 20 μl of 25 mM MgCl2, 10 μl of 10 mM dNTP mixture (2.5 mM each), 5 μl of 50 μM random hexamer, 5 μl of 20 U/μl RNase inhibitor, 5 μl of 50 U/μl Multiscribe reverse transcriptase and 45 μl of RNase-free H2O/RNA template mix. The RT-PCR reaction conditions 10min incubation at 25°C, 30min at 42°C and 5min at 99°C. The real time PCR reaction was carried out using the Fast TAQMAN PCR apparatus (Applied Biosystems) and the following reagents were used per PCR condition which was carried out in a 20 μl volume (all reagents purchased from Applied Biosystems except the water): 10 μl of 2X master mix, 1 μl of 20X TAQMAN primer-probe mix, 0.2 μl of AmpErase Uracil N-glycosylase, 0.8 μl of sterile water and 8 μl of cDNA template. The amplification conditions were as follows: 2 min at 50°C, 20 sec at 95C, followed by 40 cycles of 95°C for 1 sec and 60°C for 20 sec. All expression data was normalized for loading using human PPIA.
Cytokine and chemokine measurements
Cells were cultured in the manner described above for siRNA knockdown studies. For studies using compounds, cells were seeded as described above, but in the absence of siRNA transfection. In this case, 1 day following plating, cells were treated with Compound A, Sulphorfane, CDDO or DMSO. 1 hour after compound dosing, cells were challenged with 1 ng/ml human IL-1β, or 10 ng/ml human TNFα R+D systems, # 210-TA), or 10 ng/ml mouse IL-13 or PBS-0.1% BSA control for an additional 24 hrs. Cells were then spun down and supernatants were assayed for cytokine and chemokine using Mesoscale Discovery platform assay plates (#K111AAB-2) according to manufacturer’s protocols.
Student’s t test was performed on all data points. All data are represented as mean ± Standard Deviation.
siRNA knockdown of NRF2 and KEAP1in NHLFs
Gene expression profiling following NRF2 and KEAP1siRNA knock-down
With this analysis approach, two gene clusters (e.g. clusters 3 and 5 with 287 and 322 sequences, respectively) are differentially regulated by KEAP1 and NRF2 siRNAs.
Selecting and annotating anti-correlated NRF2 and KEAP1siRNA knock-down genes
To identify those genes whose expression was inversely regulated when comparing NRF2 and KEAP1 knockdown, genes were selected if they were modulated in the opposite direction by NRF2 and KEAP1 siRNA with combined p values less than 0.05 at 30 and 48 hours after siRNA transfection. We observed 113 common sequences between 308 and 893 signature sequences obtained from 30 and 48 hour time points; in addition, we removed a 43 gene signature specifically induced by the pool of 3 KEAP1 siRNA which is highly enriched in interferon-responsive genes and is most likely a property of that particular pool of siRNAs. Figure 2B shows a K-means clustering of the resulting 1,045 sequences which met the selection criteria with 361 sequences and 684 sequences down-regulated by NRF2 and KEAP1 siRNA, respectively. Lists of most highly down- and up-regulated genes by NRF2 siRNA at 48 hours can be found in Additional file 4.
We then queried the biological processes and pathways associated with the 893 sequences (from 48 hour time point) using resources from GO Biological Process (see Additional file 5) and Ingenuity Pathways. Additional file 6 shows Ingenuity canonical pathway analysis of the gene set derived from anti-correlated genes knocked down by NRF2 and KEAP1 siRNA, respectively. Genes involved with the most significant pathways affected by the 2 siRNA treatments (i.e. NRF2-mediated oxidative stress response and Wntβ-catenin signalling) are listed in Table 1. It is interesting to note that several Wnt/β-catenin signalling pathway genes were down-regulated by KEAP1 siRNA with the exception of WNT3 which was up-regulated 2.1 fold.
Eotaxin-1 expression is suppressed with KEAP1siRNA knockdown
KEAP1knockdown specifically inhibits Eotaxin-1 in NHLFs under inflammatory conditions
NRF2 activating compounds sulforaphane and CDDO specifically suppress IL-1β, IL-13 and TNFÎ± induced Eotaxin-1 in NHLFs
Here we present our results of microarray profiling of normal human lung fibroblast following siRNA mediated knockdown of NRF2 and KEAP1. We have identified a distinct gene set of anti-correlated genes in this analysis to better define NRF2 regulated genes in a lung specific cellular context.
A comparison of the 1,045 signature sequences differentially modulated by NRF2 and KEAP1 siRNA (Figure 2) with other gene expression signatures collected in the Gene Expression Omnibus (GEO. http://www.ncbi.nlm.nih.gov/geo/) data base indicates a highly significant anti-correlation with a gene signature obtained from primary human lung fibroblast treated with dithiothreitol (DTT) for 24 hours (Overlapping P = 1.7E-99) ; and a significant correlation with a gene set from dexamethasone-treated (24 hours) human primary osteoblast-like cells (HOb)(GEO series GSE10311.Overlapping P = 1.0E-46). In addition, we found two cigarette smoke-related gene signatures which are anti-correlated to our gene signature, one from a normal human bronchial epithelial (NHBE) cells exposed to a cigarette smoke condensate for 18 hours (Overlapping P = 2.5E-33, data derived from GEO series GSE18235 , and the other from a comparison of small airway epithelial cells between smokers and non-smokers (overlapping p = 2.3E-24) . Since DTT and cigarette smoke induce ER stress and oxidative stress, respectively; it appears that NRF2 is activated in both situations to confer cellular protection.
In addition to NRF2 promoting the anti-oxidant response machinery, this pathway also has profound anti-inflammatory effects . Studies with NRF2 deficient mice demonstrate an increased inflammatory response in several inflammatory disease models [58, 66, 67]. In respiratory models, the loss of Nrf2 results in increase eosinophil recruitment in the lungs of allergen challenged animals and the increase in lung macrophages upon hyperoxic lung injury . In models of COPD, Nrf2 deficient mice have increased neutrophil and macrophage recruitment to the lung . In vitro studies have demonstrated a specific effect of the NRF2 regulating cytokine and chemokine expression in neutrophils following LPS challenge . In addition, pharmacological activation of NRF2 with the triterpenoid CDDO can inhibit LPS induced inflammation in neutrophils and PBMCs .
In this study we make the novel discovery that Eotaxin-1 is uniquely inhibited by NRF2 activation. While the direct role of NRF2 on Eotaxin-1 regulation has not be reported previously, mice deficient for Nrf2 do have increased eosinphil recruitment to the lung upon allergen challenge associated with increased level of Eotaxin-1 in the BAL fluid . In addition, it has been demonstrated that mice with a deficiency of NADPH oxidase in non-hematopoietic cells have decreased lung eosinophilia during allergen challenge implicating the ROS in the production of Eotaxin-1 in the lung . Interestingly, it has been shown that dietary flavonoids inhibit Eotaxin-1 release from fibroblasts [69, 70]. Flavonoids have various anti-inflammatory properties and are potent inhibitors of NF-κB signalling  but are also potent activators of NRF2 . This inhibition of Eotaxin-1 observed is consistent with our study where we show inhibition of Eotaxin-1 with the triterpenoid CDDO. Based on our data with KEAP1 knockdown it can be concluded that the inhibitory effect that these flavonoids have on Eotaxin-1 is likely mediated directly by their activation of NRF2 and not through other anti-inflammatory mechanisms.
As the major eosinophil chemoattractant, Eotaxin-1 plays a critical role in allergic inflammation and asthma . In the lung Eotaxin-1 promotes the influx of eosinophils where activation and release of key mediators of an inflammatory response occurs . The role of the fibroblast in mediating eosinophil recruitment has long been established ; where it has been shown that fibroblasts derived from numerous sources secrete a significant amount of Eotaxin-1 in response to several pro-inflammatory stimuli [75–79]. Consistent with this, we have demonstrated in this report that IL-1β, IL-13 and TNFα all have potent effects on Eotaxin-1 secretion in fibroblasts. These factors are key inducers of Eotaxin-1 release and eosinophil recruitment in addition to contributing to fibrotic changes seen in airway disease [75, 79]. It would be of interest to evaluate an NRF2/ Eotaxin-1 relationship in fibroblasts from asthmatics to determine if Eotaxin-1 expression would be equally regulated by NRF2 activation is a disease state.
The mechanism by which Eotaxin-1 is modulated by NRF2 is not known. A detailed promoter study failed to identify a bonafide ARE  upstream of the human Eotaxin-1 gene, suggesting that this inhibition may be an indirect consequence of NRF2 activation. One way in which NRF2 has been shown to mediate its anti-inflammatory properties is through the inhibition of NF-κB. NRF2 and NF-κB have been shown to work together to modulate inflammatory gene expression [58, 60] and it has been suggested that NRF2 activation can lead to NF-κB inhibition [58, 81–83]. In addition it has been shown that the NF-κB pathway plays a critical role in Eotaxin-1 regulation in fibroblasts [30, 59]. While it is not clear if this is the case in our study, it is unlikely since we have demonstrated using pharmacological inhibition that all of the chemokines and cytokines induced by IL-1β and TNFα are NF-κB dependent, yet only Eotaxin-1 is inhibited by NRF2 activation.
Another key transcription factor that can mediate Eotaxin-1 expression is STAT6. A STAT6 binding site is present on the Eotaxin-1 promoter along with an NF-κB binding site and it is thought that Eotaxin-1 may be regulated by the concerted activity of NF-κB and STAT6 . STAT6 is of course a key mediator of Eotaxin-1 expression induced by IL-4 , but studies in fibroblasts have shown that STAT6 also is required for TNFα induced Eotaxin-1 expression . Thus, it remains feasible that in someway, NRF2 activation inhibits STAT6 activity, thus leading to the inhibition of Eotaxin-1 expression. There is no published data directly linking NRF2 activation to STAT6 activity, however, in one study using the licorice root triterpenoid Glycyrrhizin, it has been demonstrated that inhibition of Eotaxin-1 with this compound is associated with the inhibition of STAT6 phosphorylation and nuclear translocation . This data suggests that perhaps NRF2 does indeed regulate Eotaxin-1 expression through the regulation of STAT6 activity. Another potential mechanisms by which NRF2 may modulate Eotaxin-I expression is through modulation of MAPK signaling as it has been demonstrated that MAPK signaling downstream of TGFβ can synergize with IL-13 to induce Eotaxin-1 expression by interfering with negative feedback loops in the IL-13/STAT6 pathway . Interestingly it has been demonstrated that reactive oxygen species can directly augment the activity of STAT6  raising the possibility that a decrease in reactive oxygen species as a result of NRF2 activation may inhibit STAT6 activity and inhibit Eotaxin-1 expression.
In summary, through gene expression profiling of normal human lung fibroblasts, following siRNA knockdown of NRF2 and KEAP1, we have identified Eotaxin-1 as a novel NRF2 regulated gene. Our data further define the role of this pathway in mediating inflammatory disease in the lungs.
Nuclear factor (erythroid-derived 2)-like 2
Kelch-like ECH-associated protein 1
Chronic obstructive pulmonary disease
Anti-oxidant response elements
Small interfering Ribonucleic acid
Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
Endoribonuclease-prepared short interfering RNAs
Reverse transcription/in vitro transcription, reverse transcription/in vitro
Quantitative polymerase chain reaction
Normal human klung fibroblasts
Normal human bronchial epithelial cells
We thank Dr. Francois Gervais and Dr. Gary O’Neill for critical reading of this manuscript.
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