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. 2024 Jun 5;32(4):460–466. doi: 10.4062/biomolther.2023.194

Elafibranor PPARα/δ Dual Agonist Ameliorates Ovalbumin-Induced Allergic Asthma

Ye-Eul Lee 1, Dong-Soon Im 1,*
PMCID: PMC11214965  PMID: 38835138

Abstract

Asthma is characterized by chronic inflammation and respiratory tract remodeling. Peroxisome proliferator-activated receptors (PPARs) play important roles in the pathogenesis and regulation of chronic inflammatory processes in asthma. The role of PPARγ has been studied using synthetic PPARγ agonists in patients with asthma. However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which is a potential drug candidate for non-alcoholic fatty liver in obese patients. Elafibranor suppresses antigen-induced degranulation in RBL-2H3 mast cells without inducing cytotoxicity in vitro. In mice with OVA-induced allergic asthma, the administration of elafibranor suppressed OVA-induced airway hyper-responsiveness at a dose of 10 mg/kg. Elafibranor also suppressed the OVA-induced increase in immune cells and pro-inflammatory cytokine production in the bronchoalveolar lavage fluid (BALF). Histological studies suggested that elafibranor suppressed OVA-induced lung inflammation and mucin hyper-production in the bronchial airways. In addition, elafibranor suppressed OVA-induced increases in serum immunoglobulin E and IL-13 levels in BALF. Conversely, the present study suggests that elafibranor has the potential for use in patients with allergic asthma.

Keywords: Asthma, Allergy, Elafibranor, Immunopharmacology, PPAR

INTRODUCTION

The prevalence of allergic asthma in children and young adults has increased in developed countries (Dharmage et al., 2019). Asthma is characterized by chronic inflammation and respiratory tract remodeling (Fehrenbach et al., 2017). Chronic inflammatory responses and remodeling processes in the airways are the main pathogeneses evoked by immune cells during the development of asthma (Fehrenbach et al., 2017). In the chronic stage of asthma, Th2, Th1, and Th17 immune responses are mixed and interconnected (Luo et al., 2022). Allergen-induced airway hyper-responsiveness (AHR) and mucin hyperproduction are followed by airway wall remodeling (Fehrenbach et al., 2017). The current therapies include locally inhaled steroids, long-acting β2 agonists, and orally administrated leukotriene pathway blockers (Chung et al., 2009). Alternative options are needed for patients with severe asthma who are resistant to current therapies.

Considering the continuous injury and the subsequent repair mechanisms in the airway wall, therapeutic agents that act on anti-inflammatory nuclear receptors may be a good choice. Peroxisome proliferator-activated receptors (PPARs) play an important role in the pathogenesis and regulation of chronic inflammatory processes. As PPARs have anti-inflammatory properties by inhibiting nuclear factor-κB (NF-κB), synthetic agonists of PPARγ such as rosiglitazone and pioglitazone have been clinically studied in patients with asthma (Richards et al., 2010; Dixon et al., 2015; Anderson et al., 2016; Kaler et al., 2017; Nobs et al., 2017). However, involvement of PPARα/δ has not been studied in asthma. In the present study, we investigated if elafibranor, a PPARα/δ dual agonist, can modulate ovalbumin (OVA)-induced allergic asthma, which has been clinically tested for treatment of dyslipidemia, hyperglycemia, insulin resistance, and non-alcoholic fatty liver in obese patients (Cariou et al., 2011, 2013; Ratziu et al., 2016).

MATERIALS AND METHODS

Materials

Elafibranor was purchased from MedChemExpress (Cat no. HY-16737, Monmouth Junction, NJ, USA). OVA, albumin from chicken egg white (A5503, CAS number 9006-59-1, lot number SLCK7421) and alum were obtained from Sigma-Aldrich (St. Louis, MO, USA).

Cell culture

Rat RBL-2H3 mast cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). The cells were cultured at 37°C in 5% CO2 in a humidified incubator and maintained in Dulbecco’s modified Eagle medium (DMEM)-high glucose containing 10% (v/v) heat-inactivated fetal bovine serum along with 2 mM glutamine, 100 U/mL penicillin, 1 mM sodium pyruvate, and 50 μg/mL streptomycin.

Animals

Daehan Biolink Co. Ltd. (Seoul, Korea) provided five-week-old female BALB/c mice. The mice were housed in a laboratory animal facility at Kyung Hee University (Seoul, Korea) and provided water and food ad libitum. The Institutional Animal Care Committee of the university reviewed and approved the study protocol (Approval Number, KHSASP-23-420).

MTT assay

RBL-2H3 cells were plated in 96-well plates at a density of 1×105 cells per well. After incubation for 24 h, the medium was changed to fresh medium containing elafibranor (0.1-30 μM), or vehicle (10% DMSO). After incubating for 24 h, 100 μL of 10% MTT-containing solution was added. After incubating for 4 h, the media was removed and 100 μL of DMSO was added to dissolve the formazan crystals formed by MTT. Absorbance is measured at 570 nm.

Assessment of degranulation

Degranulation of RBL-2H3 cells was assessed by measuring the β-hexosaminidase activity in the medium. Mouse monoclonal anti-dinitrophenyl immunoglobulin E (DNP-IgE) and human DNP albumin were used to induce degranulation.

Asthma induction in mice and elafibranor administration

Six-week-old female BALB/c mice were divided into four treatment groups (n=5): a PBS-injected control group, an OVA-induced asthma group, an OVA-induced asthma group treated with elafibranor (3 mg/kg), and an OVA-induced asthma group treated with elafibranor (10 mg/kg). Sensitization was by intraperitoneal injection of 50 μg OVA and 1 mg aluminum hydroxide on the day 0 (D0) and D14 (sensitization). OVA exposure was by delivery of nebulized 1% OVA or PBS for 30 min using an ultrasonic nebulizer (Philips) on D28, D29, and D30 (challenge). Elafibranor was administered via intraperitoneal injection 30 min before OVA challenge (D28, D29, and D30). Bronchoalveolar lavage fluid (BALF) was collected from lungs on D32, and the population of BALF cells was analyzed after staining (Lee and Im, 2021).

BALF cell counting and analysis

The immune cells in the BALF were made to adhere to a glass slide using Cellspin® centrifuge (Hanil Electric, Seoul, Korea) and then fixed in MeOH for 30 s. The cells were stained with May-Grünwald solution for 8 min, followed by Giemsa solution for 12 min. BALF cells were distinguished based on their size, color, and granularity and counted by two independent experts. The largest blue-stained cells are macrophages, while eosinophils are average size and have purple-colored granules. Small and deep-blue stained cells are lymphocytes.

Measuring AHR to methacholine

The day after the final OVA challenge, AHR was evaluated using a non-invasive lung function measurement Model PLY-UNR-MS2 (EMKA Technologies, Paris, France). After placing the mice in a barometric plethysmographic chamber, the baseline was recorded for 3 min and the enhanced pause (Penh) was calculated according to the manufacture’s protocol. The results are expressed as the percentage increase in Penh following challenge with increasing concentrations of methacholine (0, 6.25, 12.5, 25 and 50 mg/mL).

Histological examination of the lung

Lung tissue sections prepared from the lungs were stained with hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) to evaluate immune cell infiltration and mucus-producing cells, respectively.

A treatment-blind observer measured the degree of lung inflammation on a subjective scale of 0-3. PAS-stained mucin-secreting cells around the bronchioles were counted in two lung sections per mouse. Mucous production was expressed as the number of PAS-positive cells per millimeter of bronchiole after measuring the length of the bronchial basal lamina using ImageJ software (National Institute of Health, Bethesda, MD, USA).

Measurement of the levels of total serum IgE and IL-13

Serum IgE and bronchoalveolar lavage fluid (BALF) IL-13 levels in the mice were evaluated using ELISA kits (eBioscience, San Diego, CA, USA). Capture and biotinylated detection antibodies specific for IL-13 were obtained from eBioscience (Cat no. 14-7043-68 and 33-7135-68B). The absorbance was measured at 450 nm.

Statistics

The statistical analyses were performed using GraphPad Prism software (GraphPad Software, Inc., La Jolla, CA, USA). One-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test was used to compare the differences among multiple groups. Data are expressed as means ± standard error of the mean (SEM). Differences were considered statistically significant at p<0.05.

RESULTS

Elafibranor suppressed degranulation of RBL-2H3 mast cells

After antigen sensitization, mast cells trap circulating IgE on FcεRI complexes and respond to antigens by cross-linking FcεRI, resulting in degranulation of vesicles (Ando and Kitaura, 2021). This leads to the releases of vesicle-stored allergic mediators, such as histamine, leukotriene D4, chemokines, cytokines, and neutral proteases (Ando and Kitaura, 2021). The most popular method for assessing mast cell degranulation is to measure β-hexosaminidase activity in RBL-2H3 mast cells after exposure to human serum albumin (HSA, antigen) (Rujitharanawong et al., 2022). Elafibranor inhibited HSA-induced release of β-hexosaminidase in a concentration-dependent manner (Fig. 1A). Significant elafibranor-induced inhibition on RBL-2H3 cell degranulation was observed at concentrations of 10 and 30 μM (Fig. 1A). The concentrations of elafibranor used were not cytotoxic to RBL-2H3 cells up to 30 μM in an MTT cell viability assay (Fig. 1B).

Fig. 1.

Fig. 1

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Effects of elafibranor treatment on airway hyper-responsiveness to methacholine in OVA-induced murine asthma model. (A) Schematic drawing of experimental time course. (B) Airway hyper-responsiveness was measured as Penh (enhanced pause) in mice treated with elafibranor (3 or 10 mg/kg) or PBS after challenge with increasing concentrations of methacholine. PBS: PBS-treated mice, OVA: OVA-challenged mice, OVA+elafibranor (3 mg/kg), and OVA+elafibranor (10 mg/kg). Results are presented as means ± standard error of mean (SEM) (n=5). *p<0.05, **p<0.01 vs. PBS-treated group, #p<0.05, ##p<0.001 vs. OVA-treated group.

Effects of elafibranor on AHR during OVA-induced asthma

The in vitro suppressive effects of elafibranor on RBL-2H3 cell degranulation was investigated in an OVA-induced allergic asthma model of BALB/c mice in vivo. Elafibranor (3 or 10 mg/kg) was injected intraperitoneally 30 min before the OVA challenge (Fig. 2). By using whole body plethysmography, increases in enhanced pause (Penh) were measured as an index of airway obstruction in unrestrained and conscious mice (Hamelmann et al., 1997). Penh values were measured by increasing the methacholine dosage, and these values were interpreted as measurements of AHR (Hamelmann et al., 1997). Mice with OVA-induced allergic asthma showed significantly increased Penh values at methacholine dosages (12.5, 25, and 50 mg/mL) compared to those in PBS-treated control mice, suggesting that asthma induction was successful. Elafibranor treatment reduced the increase in Penh values in OVA-treated mice in a dose-dependent manner (Fig. 2). Treatment with 3 mg/kg elafibranor tended to reduce Penh values, but this was not statistically significant (Fig. 2). Statistical significance was observed at a 10 mg/kg dose of elafibranor from 12.5 to 50 mg/mL methacholine compared to the PBS-treated control group (Fig. 2).

Fig. 2.

Fig. 2

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Elafibranor reduces antigen-induced degranulation in RBL-2H3 mast cells. (A) After sensitization with anti-dinitrophenyl immunoglobulin E (DNP-IgE) for 18 h, RBL-2H3 cells were challenged with dinitrophenyl-human serum albumin (DNP-HSA). Elafibranor treatment was performed at the indicated concentrations 30 min before antigen challenge. Basal degranulation shows samples without IgE and HSA, and the positive control of antigen-induced degranulation shows samples with IgE and HSA. (B) Cell viability was determined by using MTT assay in rat RBL-2H3 mast cells. The absorbance was measured at 570 nm. Results are presented as means ± standard error (SE) of three independent experiments. ***p<0.001 vs. HSA-untreated group. #p<0.05, ###p<0.01 vs. HSA-treated group.

Elafibranor suppressed increase in immune cell counts in the BALF

Accumulation of immune cells occurs in the BALF after antigen challenge. Therefore, immune cells in the BALF were collected 48 h after the last OVA challenge and analyzed. The number of immune cells was higher in the BALF of the OVA-treated group than in the PBS-treated control group (Fig. 3A). Elafibranor treatment decreased the number of immune cells in a dose-dependent manner (Fig. 3A). Elafibranor-induced suppression was quantitatively analyzed by counting the total cell number and analyzing each population (Fig. 3B-3E). The total cell number was significantly reduced by elafibranor treatment in a dose-dependent manner (Fig. 3B). Although the macrophage numbers did not change after OVA or elafibranor treatment (Fig. 3C), the numbers of eosinophils and lymphocytes were greatly increased by OVA treatment and suppressed by elafibranor in a dose-dependent manner (Fig. 3D, 3E).

Fig. 3.

Fig. 3

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Elafibranor inhibits OVA-induced immune cell accumulation in BALF. (A) Mice were sensitized with OVA twice by i.p. injection on D0 and D14 and were subsequently challenged on D28, D29, and D30 with nebulized OVA. Elafibranor was administrated intraperitoneally at a dose of 3 or 10 mg/kg 30 min before OVA challenge. Cells in BALF were stained using May-Grünwald stain and counted. (B) Total cell counts in BALF. (C) Macrophages in BALF. (D) Eosinophils in BALF. (E) Lymphocytes in BALF. Results are presented as means ± SEM cell count values (n=5). ***p<0.001 vs. PBS-treated group, ##p<0.01, ###p<0.001 vs. OVA-treated group.

Elafibranor suppressed morphologic changes and inflammation in lungs

Histological changes in asthma were assessed in lung samples using H&E and PAS staining. In the H&E-stained sections, OVA exposure increased the number of immune cells, mainly eosinophils, around the peribronchial regions (Fig. 4A), which were rarely observed in the PBS-treated control group. The accumulation of immune cells was suppressed in H&E-stained sections from the elafibranor-treated group (Fig. 4A). Lung inflammation was assessed using a subjective scale of 0-3. In PAS-stained sections, mucin hypersecretion was increased in the OVA-treated group, which was shown as violet-colored goblet cells surrounding the bronchioles (Fig. 4B), suggesting hyperplasia of goblet cells. PAS-stained cells were rarely observed in the PBS-treated group (Fig. 4B). Elafibranor treatment significantly reduced the violet color in a dose-dependent manner (Fig. 4B). The average inflammation score in the OVA-treated group was approximately 2.3, which was significantly suppressed by elafibranor treatment in a dose-dependent manner (Fig. 4C). Mucin production was semi-quantitatively analyzed by measuring the number of PAS-positive cells in the bronchioles (Fig. 4D). There were approximately 115 PAS-positive cells/mm in the OVA-treated group, and this number was significantly reduced by elafibranor treatment in a dose-dependent manner (Fig. 4D).

Fig. 4.

Fig. 4

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Elafibranor protects against airway inflammation and mucin production. (A) H&E-stained sections of lung tissues from PBS, OVA, and elafibranor (3 or 10 mg/kg)-treated OVA groups. Small navy-blue dots around bronchioles are eosinophils. Eosinophils were rarely observed in PBS group, whereas they accumulated extensively around bronchioles in OVA group (green arrows). (B) Periodic acid-Schiff (PAS)/hematoxylin-stained sections of lung tissues from the PBS, OVA, and elafibranor (3 or 10 mg/kg)-treated OVA groups. In PAS staining, mucin is stained purple. In OVA group, a darker and thicker purple color was observed surrounding bronchioles compared to PBS group (red arrows). Eosinophil accumulation was less pronounced in OVA+elafibranor group than in OVA group. (C) Lung inflammation was semi-quantitatively evaluated; histological findings were scored as described in Materials and Methods. (D) Mucous production was evaluated by counting number of PAS-positive cells (red arrows) per mm of bronchioles (n=5 per group). Values represent means ± SEM (n=5). ***p<0.001 vs. PBS-treated group, ##p<0.01, ###p<0.001 vs. OVA-treated group.

Elafibranor inhibited asthma-induced cytokine expression in BALF

Both Th2 and Th1/Th17 cells play key roles in the chronic stage of asthma. In addition to the Th2 pro-inflammatory cytokines, IL-4 and IL-13, the Th1/Th17 cytokines, IFN-γ and IL-17A, were measured by qPCR in BALF cells. The mRNA levels of these four cytokines in BALF immune cells were significantly increased in the BALF cells of the OVA group compared to those in the PBS group (Fig. 5). Elafibranor treatment significantly suppressed the increase in the levels of these four cytokines at both doses (Fig. 5).

Fig. 5.

Fig. 5

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Elafibranor treatment inhibits mRNA expression of cytokines in BALF cells. Analysis of mRNA expression of Th2 cytokines IL-4 and IL-13, Th1 cytokine IFN-γ, and Th17 cytokine IL-17A in BALF cells. (A) IL-4, (B) IL-13, (C) IFN-γ, and (D) IL-17A levels. mRNA levels of cytokines were quantified relative to GAPDH. The values are represented as means ± SEM (n=5). *p<0.05, **p<0.01, ***p<0.001 vs. PBS-treated group, #p<0.05, ##p<0.01, ###p<0.001 vs. OVA-treated group.

Elafibranor suppressed OVA-induced increase of IL-13 levels in BALF and serum IgE titers

To determine the changes in the mRNA levels of Th2 cytokines, the protein levels of IL-4 and IL-13 in BALF were assessed using ELISA. Elevated IL-13 levels were seen in the OVA-treated group compared to those in the PBS-treated control group, and the increase in IL-13 levels was significantly reduced by treatment of 10 mg/kg elafibranor (Fig. 6A). The protein levels of IL-4 were below the detection limit of the ELISA (data not shown). IgE levels were measured in the serum, as serum IgE levels were increased in patients with asthma. Serum IgE levels were significantly higher in the OVA-treated group than those in the PBS group (Fig. 6B). However, the OVA-induced increase in serum IgE concentration was significantly suppressed in the elafibranor-treated group compared to the OVA group after treatment with 10 mg/kg elafibranor (Fig. 6B).

Fig. 6.

Fig. 6

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Effects of elafibranor on IL-13 levels in BALF and IgE levels in serum. ELISA was used to measure protein levels of IL-13 in BALF (A) and IgE in serum (B). Results are presented as means ± SEM (n=5). ***p<0.001 vs. PBS-treated group, #p<0.05, ###p<0.001 vs. OVA-treated group.

DISCUSSION

Elafibranor was developed for the treatment of dyslipidemia and impaired glucose metabolism in obese and diabetic patients (Cariou et al., 2011; Westerouen Van Meeteren et al., 2020). Elafibranor improves hepatic and peripheral insulin sensitivity in abdominally obese subjects (Cariou et al., 2013; Khan et al., 2019). In addition, elafibranor induced resolution of non-alcoholic steatohepatitis without fibrosis worsening (Ratziu et al., 2016; Tacke and Weiskirchen, 2021). However, its application in allergic asthma has not yet been investigated. In the present study, we found that elafibranor has a therapeutic effect on OVA-induced allergic asthma in mice and a suppressive effect on antigen-induced mast cell degranulation. As elafibranor is a dual activator of PPARα/δ, both PPARα and PPARδ should be involved in its anti-allergic asthma effects. PPARα is expressed in epithelial cells, macrophages, lymphocytes, and dendritic cells (Contreras et al., 2013). Furthermore, activation of PPARα not only reduces the production of pro-inflammatory mediators such as IL-1, IL-6, IL-8, and TNF-α but also induces the production of anti-inflammatory IL-10 (Contreras et al., 2013). Thus, elafibranor activation of PPARα must contribute to its anti-asthma effects by its regulation of inflammatory responses. In contrast, PPARδ is expressed in all organs and tissues (Neels and Grimaldi, 2014). Activation of PPARδ results in the oxidation of fatty acids, normalization of plasma lipids, regulation of blood glucose, and sensitization of cells to insulin, preventing the development of obesity (Neels and Grimaldi, 2014). The activation of PPARδ also promotes the disruption of NF-κB function by suppressing the binding of NF-κB to DNA (Neels and Grimaldi, 2014; Su et al., 2014). In addition, binding of PPARα to NF-κB has been shown to lead to the proteolytic degradation of NF-κB (Hou et al., 2012; Cheng et al., 2018). Therefore, dual activation of PPARα/δ by elafibranor may suppress the pro-inflammatory functions of NF-κB, resulting in suppression of allergic asthma (Hou et al., 2012; Su et al., 2014; Cheng et al., 2018).

In clinical trials, the PPARγ agonist rosiglitazone was associated with decreased levels of inflammatory markers (Richards et al., 2010), whereas pioglitazone did not show significant efficacy in patients with mild and severe asthma (Dixon et al., 2015; Anderson et al., 2016; Kaler et al., 2017). If elafibranor is found to be applicable to human asthma, it would be a novel drug discovery.

ACKNOWLEDGMENTS

This research was supported by the Basic Science Research Program of the Korean National Research Foundation funded by the Korean Ministry of Science, ICT, and Future Planning (NRF-2023R1A2C2002380).

Footnotes

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

AUTHOR CONTRIBUTIONS

YE Lee and DS Im: Designed the experiments; YE Lee: Performed the experiments and analyzed the data; DS Im: Wrote the manuscript.

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