Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone

Richard A Johnston; Constance L Atkins; Saad R Siddiqui; William T Jackson; Nicholas C Mitchell; Chantal Y Spencer; Albert W Pilkington, 4th; Michael L Kashon; Ikram U Haque

doi:10.1152/ajpregu.00213.2022

. 2022 Oct 25;323(6):R921–R934. doi: 10.1152/ajpregu.00213.2022

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone

Richard A Johnston ^1,^2,^3,^✉, Constance L Atkins ⁴, Saad R Siddiqui ², William T Jackson ², Nicholas C Mitchell ², Chantal Y Spencer ⁵, Albert W Pilkington 4th ¹, Michael L Kashon ¹, Ikram U Haque ²

PMCID: PMC9722265 PMID: 36283092

Abstract

Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O₃), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O₃, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O₃-exposed IL-11Rα1-deficient as compared with O₃-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O₃-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O₃ exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.

Keywords: adiponectin, airway hyperresponsiveness, asthma, coefficient of lung tissue elastance, interleukin-11

INTRODUCTION

Interleukin (IL)-11 is a pleiotropic, cationic cytokine that is expressed by a plethora of cells: chondrocytes, endothelial and epithelial cells, eosinophils, fibroblasts, neurons, osteoblasts, smooth muscle cells, spermatids, synoviocytes, and trophoblasts (1–10). As a multifunctional cytokine, IL-11 regulates a diverse number of biological processes, such as adipogenesis, fertility, fibrosis, hematopoiesis, inflammation, metastasis, neurogenesis, and osteoclastogenesis (11–16). To transduce classic signaling in humans, IL-11 requires, in part, the presence of IL-11 receptor subunit α (IL-11Rα), which is a transmembrane receptor that is part of the type I cytokine receptor family (12, 17, 18). Consistent with the pleiotropic effects of IL-11, IL-11Rα or its murine homolog [IL-11 receptor subunit α-1 (IL-11Rα1)] is expressed by several diverse cell populations, including adipocyte-like cells, decidual cells, epithelial cells, lymphocytes, megakaryocytes, oligodendrocytes, osteoblasts, osteoclasts, smooth muscle cells, stellate cells, and stromal cells (19–28).

IL-11 binds with low affinity to IL-11Rα on the plasma membrane, yet this interaction is inadequate to initiate classic signaling (12). However, in accordance with its membership in the IL-6 family of cytokines, IL-11 also requires glycoprotein (gp) 130 for effective signal transduction (29). Thus, after IL-11 binds to IL-11Rα, it creates a high-affinity complex with gp130, which results in gp130 dimerization and the formation of a heterohexameric complex that consists of two molecules of IL-11, IL-11Rα, and gp130 (2, 12, 18). Once this six-member receptor complex is created, IL-11 signal transduction commences with activation of the Janus kinase-signal transducer and activator of the transcription (STAT) pathway (12, 18). Finally, the ectodomain of IL-11Rα can be cleaved from the plasma membrane by ADAM10, a sheddase, to generate a soluble form of IL-11Rα that can elicit trans-signaling along with IL-11 and membrane-bound gp130 in cells that do not express IL-11Rα (30, 31).

A single gene encodes the IL-11Rα protein in humans [interleukin 11 receptor subunit α (IL11RA)] and the IL-11Rα1 protein in mice [interleukin 11 receptor, α chain 1 (Il11ra1)] (32, 33). Present in select strains of mice, however, is the interleukin 11 receptor, α chain 2 (Il11ra2) gene, which encodes a protein and second receptor for IL-11 [IL-11 receptor subunit α-2 (IL-11Rα2)] (34, 35). Despite impressive semblance between the coding sequences of the Il11ra1 and Il11ra2 genes, the expression pattern of these genes is quite dissimilar (36). Specifically, Il11ra1 messenger ribonucleic acid (mRNA) is expressed in numerous tissues and organs, such as bone marrow, brain, heart, kidney, and lung, whereas expression of Il11ra2 mRNA is more restricted to the lymph nodes, testes, and thymus (34, 36). Although IL-11 binds IL-11Rα1 and IL-11Rα2 with similar affinity (34, 37), no published data are in existence concerning the signaling capabilities of IL-11Rα2.

Asthma is a chronic respiratory disease that is characterized, in part, by cough, dyspnea, wheeze, airway remodeling, mucous metaplasia, persistent lung inflammation, variable expiratory airflow limitation, and airway hyperresponsiveness (AHR) to nonspecific bronchoconstrictors, including methacholine chloride, histamine acid phosphate, and leukotriene E₄ (38–40). As a heterogeneous lung disease, asthma materializes as a diverse number of phenotypes such as atopic, nonatopic, obesity-related, and smoking-associated (39, 41). Minshall et al. (4) previously reported that expression of IL11 mRNA was greater in lung tissue of subjects with asthma as compared with nonasthmatic subjects, an observation that suggests that IL-11 may contribute to the pathogenesis of asthma. Indeed, in the absence of any inciting stimulus, administration of recombinant human IL-11 to BALB/c mice via nasal insufflation causes AHR, whereas overexpression of IL11 mRNA in a lung-specific fashion leads to airway wall thickening, peribronchiolar inflammation, subepithelial lung fibrosis, and AHR (11, 42). Furthermore, Lee et al. (16) demonstrated that eosinophilic lung inflammation, T-helper cell type-2 cytokine expression, and goblet cell hyperplasia are significantly reduced in antigen-sensitized and challenged mice that do not express IL-11Rα1. In many strains of mice, antigen sensitization and challenge leads to a phenotype that mimics many of the characteristic features of atopic asthma in humans (43).

Atopic asthma is often distinguished from other asthma phenotypes by its early onset, the presence of antigen-specific immunoglobulin E (IgE), allergenic provocation, and demonstrable, positive responsiveness to corticosteroids, whereas nonatopic asthma is uniquely identified by its late onset, the absence of antigen-specific IgE, female preponderance, and poor responsiveness to corticosteroids (44, 45). As described in the preceding paragraph, Lee et al. (16) reported the contribution of IL-11Rα1 to the development of atopic lung inflammation. However, the involvement of IL-11Rα1 in the manifestation of lung inflammation and AHR induced by a nonatopic asthma stimulus in mice has not been addressed.

Ozone (O₃) is a common air pollutant, an impressively efficacious oxidant, and a nonatopic asthma stimulus. Globally, in 2015, a minimum of nine million emergency room visits for asthma were attributed to O₃ (46). By reacting with unsaturated fatty acids in the lung lining fluid, O₃ initiates a cascade of chemical reactions that generate lipid peroxides and protein adducts in the plasma membrane of lung epithelial cells (47). When structurally important plasma membrane lipids and proteins are altered via peroxidation and adduction, respectively, cell injury ensues by disruption of transmembrane ion gradients and by impairment of cellular metabolism (48). In response to this injury, lung inflammation emanates, which is notably characterized by the presence of proinflammatory cytokines [e.g., IL-6, keratinocyte chemoattractant (KC), macrophage inflammatory protein (MIP)-2, and osteopontin] and soluble tumor necrosis factor receptor (sTNFR) 1 and 2 in bronchoalveolar lavage (BAL) fluid (49–51). Furthermore, many of the aforementioned cytokines are required for the migration of neutrophils to the lungs and for AHR, which are the principal pathological features induced by acute exposure to O₃ (49–54).

Because IL-11Rα1 is necessary for maximal lung inflammation induced by atopic asthma stimuli and because IL-11 causes AHR, we hypothesized that IL-11Rα1 is also required for the manifestation of lung inflammation and AHR induced by O₃, a nonatopic asthma stimulus. To that end, we exposed wild-type mice and mice homozygous for a null mutation in the gene encoding Il11ra1 (IL-11Rα1-deficient mice) to either filtered room air (air) or O₃ [2 parts/million (ppm)] for 3 h, and subsequent to the cessation of exposure, we assessed lung inflammation and airway responsiveness in the experimental animals.

MATERIALS AND METHODS

Animals

IL-11Rα1-deficient mice were generated via homologous recombination by replacing exons 9 through 12 and parts of exons 8 and 13 of the Il11ra1 gene with a phosphoglycerate kinase 1 (PGK1) promoter-aminoglycoside 3'-phosphotransferase (neo) gene construct (55). IL-11Rα1-deficient mice are viable and demonstrate no abnormalities in hematopoietic and nonhematopoietic organs or in complete blood counts when compared with wild-type mice and mice heterozygous for a null mutation in the gene encoding Il11ra1 (IL-11Rα1^+/− mice) (55).

To generate IL-11Rα1-deficient mice for this study, two breeding phases were executed. First, two breeding pairs of IL-11Rα1^+/− mice (Strain No. 004621) were purchased from The Jackson Laboratory (Bar Harbor, ME). Among the offspring of these mice, we identified, at the Il11ra1 allele, wild-type, IL-11Rα1^+/−, and IL-11Rα1-deficient mice via genotyping by polymerase chain reaction (PCR). Second, because IL-11Rα1-deficient female mice are infertile (27), all subsequent breeding pairs consisted of IL-11Rα1-deficient male and IL-11Rα1^+/− female mice to produce IL-11Rα1-deficient mice for our experiments.

Progeny of breeding pairs was genotyped for Il11ra1 alleles as follows. First, genomic DNA was extracted from a tail snip using the HotSHOT method (56). Second, an aliquot of genomic DNA was added to a solution containing KAPA2G Fast Genotyping Mix (Kapa Biosystems, Inc.; Wilmington, MA) and a common sense primer (5′- GGCTCCCGTCATTACCTACA-3′) and specific antisense primers for the wild-type (5′- AGCAGTCCTACCCGCTACAA-3′) and mutant (PGK1-neo-containing; 5′- ACTTGTGTAGCGCCAAGTGC-3′) Il11ra1 alleles. Following amplification of genomic DNA via PCR using the aforementioned primers, the PCR amplicons were visualized on a 1.8% ethidium bromide-stained agarose gel using a GelVue ultraviolet transilluminator (Model Number GV2M30; Syngene, Cambridge, UK). The primers produced a wild-type amplicon of 766 base pairs (bp) and a mutant amplicon of 593 bp. Figure 1 illustrates a representative ethidium-bromide-stained agarose gel containing Il11ra1 amplicons generated from wild-type, IL-11Rα1^+/−, and IL-11Rα1-deficient mice.

Figure 1. — Representative interleukin 11 receptor, α chain 1 (*Il11ra1*) amplicons generated from the progeny of *IL-11Rα1*^+/− breeding pairs. As described in materials and methods, genomic DNA was extracted from tails snips obtained from wild-type mice, mice heterozygous for a null mutation in *Il11ra1* (*IL-11Rα1*^+/− mice), and mice homozygous for a null mutation in *Il11ra1* (IL-11Rα1-deficient mice) and amplified via PCR using specific primers for the *Il11ra1* wild-type and mutant alleles. PCR products were resolved on a 1.8% ethidium bromide-stained agarose gel. Amplification of genomic DNA via PCR from 1) wild-type mice generated one amplicon of 766 base pairs (bp), 2) *IL-11Rα1*^+/− mice generated two amplicons of 766 and 593 bp, and 3) IL-11Rα1-deficient mice generated one amplicon of 593 bp.

Because IL-11Rα1-deficient mice were backcrossed into a C57BL/6J background for at least 12 generations, age- and sex-matched C57BL/6J mice (Strain No. 000664) were used as wild-type controls and purchased from The Jackson Laboratory. All breeding pairs and their progeny as well as wild-type mice were housed in the same room within a larger multispecies, modified barrier animal care facility at McGovern Medical School at The University of Texas Health Science Center at Houston (Houston, TX) under conditions we previously described (57). For all experiments, male C57BL/6J and IL-11Rα1-deficient mice between 8 and 20 wk of age were used. The care and use of all animals in this study adhered to the guidelines of the National Institutes of Health (Bethesda, MD), and each of the experimental protocols used in this study was approved by the Animal Welfare Committee of The University of Texas Health Science Center at Houston (Houston, TX).

Protocol

Two separate cohorts of mice were used in this study. In the first cohort, mice were euthanized 4 or 24 h after cessation of a 3-h exposure to either air or O₃ (2 ppm), and blood, BAL fluid, and lungs were subsequently obtained from these animals. Data from air‐exposed, genotype‐matched mice in this cohort were pooled for each outcome indicator that was assessed at 4 or 24 h after cessation of exposure. In the second cohort, mice were anesthetized 24 h after cessation of a 3-h exposure to either air or O₃ (2 ppm), and quasistatic respiratory system pressure-volume (PV) curves were then generated from each mouse before measurement of airway responsiveness to acetyl-β-methylcholine chloride (methacholine).

Air and O₃ Exposures

Each mouse was removed from its microisolator cage, weighed, and placed in its own cell that was part of a larger stainless steel wire mesh cage, which was then positioned inside a powder-coated aluminum and Plexiglas exposure chamber. Without access to food or water, mice were subsequently exposed to either air or O₃ (2 ppm) for 3 h. After the exposure ceased, mice were returned to the microisolator cage they occupied before the exposure until either 4 or 24 h after cessation of exposure. Mice were weighed again immediately before euthanasia or anesthesia. A detailed description of the air- and O₃-exposure system has been previously described by us (49).

Finally, when the sensitivity to inhaled O₃ was assessed in nine genetically diverse inbred strains of mice, C57BL/6J and 129S1/SvlmJ mice were categorized as “highly sensitive” since both strains exhibited profound lung inflammation and increases in airway responsiveness as compared with seven other inbred strains after acute exposure to O₃ (58). Thus, C57BL/6J mice and genetically altered mice backcrossed into a C57BL/6J background, including IL-11Rα1-deficient mice, are invaluable tools to assess O₃-induced lung pathophysiology.

Blood Collection, BAL, and Lung Harvest

Mice in the first cohort were euthanized with an intraperitoneal injection of pentobarbital sodium (200 mg/kg; Vortech Pharmaceuticals, Ltd., Dearborn, MI) 4 or 24 h after cessation of exposure to either air or O₃. Once the animal failed to elicit ocular and pedal withdrawal reflexes, a median thoracotomy was performed, and blood was collected from the right ventricle of the heart. Serum was subsequently isolated from the blood and stored at −20°C until needed. After blood was collected, the lungs were lavaged a total of four times with ice-cold lavage buffer [1× phosphate-buffered saline (PBS) containing 0.6 mM ethylenediaminetetraacetic acid]. The lavagates were pooled, the liquid and cellular components of the lavagate separated by centrifugation, and the supernatant stored at −80°C until needed. The cell pellet that remained after centrifugation was resuspended in 1 mL of Hanks’ balanced salt solution (HyClone Laboratories, Logan, UT), and the total number of cells in this suspension was enumerated with a hemacytometer (Hausser Scientific; Horsham, PA). For differential cell analysis, BAL cells were first deposited onto microscope slides using a CytoZEN cytology centrifuge (Hettich Instruments; Beverly, MA). Subsequently, the slides were air-dried and stained with the Hema 3 stain set (Fisher Diagnostics; Middletown, VA). The cells that were deposited onto the slides were examined under a light microscope at a total magnification of ×400 for differential counts. Finally, when lavages were complete, the animal’s circulation was flushed with 10 mL of ice-cold 1× PBS, the left main bronchus severed, and the left lung removed from the animal and snap-frozen in liquid nitrogen and stored at −80°C until needed for ribonucleic acid (RNA) extraction. These experimental methods have been previously described by us in extensive detail (57).

RNA Extraction, cDNA Synthesis, and Reverse Transcription-Quantitative Real-Time Polymerase Chain Reaction

Using previously described methods (57, 59), total RNA was extracted from frozen lung tissue, complementary cDNA was synthesized from mRNA, quantitative polymerase chain reaction (qPCR) was performed, and data were analyzed using the comparative threshold cycle method so that the relative abundance of Il11ra1 mRNA 4 or 24 h after cessation of exposure to O₃ was expressed relative to the abundance of Il11ra1 mRNA after cessation of exposure to air. All data were normalized to the abundance of hypoxanthine-guanine phosphoribosyl transferase (Hprt) mRNA, a reference gene (60). Primers for murine Il11ra1 and Hprt were purchased from Qiagen (Germantown, MD) and Bio-Rad Laboratories, Inc. (Hercules, CA), respectively.

Cytokine and Protein Quantification

BAL supernatant and/or serum IL-11, adiponectin, IL-6, KC, macrophage inflammatory protein (MIP)-3α, hyaluronan, osteopontin, and sTNFR 1 and 2 were quantified by either Quantikine or DuoSet ELISA kits according to the manufacturer’s instructions (R&D Systems, Inc.; Minneapolis, MN). Total BAL protein was quantified using the Bio-Rad protein assay (Bio-Rad Laboratories, Inc.) as previously described (57).

Quasi-Static Respiratory System PV Curves and Airway Responsiveness to Methacholine

Twenty-four hours after cessation of exposure to either air or O₃, mice were 1) anesthetized with pentobarbital sodium (50 mg/kg; Oak Pharmaceuticals, Inc.; Lake Forest, IL) and xylazine hydrochloride (7 mg/mL; Vedco Inc.; St. Joseph, MO), 2) tracheostomized with an 18-gauge tubing adaptor (Becton, Dickinson and Company; Franklin Lakes, NJ), and 3) ventilated at a frequency of 2.5 Hz, a tidal volume of 0.3 mL, and a positive end-expiratory pressure of 3 cmH₂O for the generation of quasi-static respiratory system PV curves and the measurement of airway responsiveness to methacholine (Sigma Aldrich, Inc.; St. Louis, MO) as we previously described (49, 61). From each PV curve, A, an estimate of inspiratory capacity; K, curvature of the upper portion of the expiratory limb of the PV curve; C_stat, quasi-static respiratory system compliance; and area, respiratory system hysteresis, were calculated. A, K, and C_stat were determined using the Salazar–Knowles equation (62, 63). After the generation of PV curves was complete, respiratory system impedance (Z_RS) was determined using the forced oscillation technique as we and others have previously described (49, 64–66). The constant-phase model was used to partition Z_RS into components representing airway resistance (R_aw), the coefficient of lung tissue damping (G), and the coefficient of lung tissue elastance (H) after administration of 1× PBS (Sigma Aldrich, Inc.) alone and after administration of increasing concentrations of methacholine dissolved in 1× PBS (0.1–100 mg/mL) (49, 64). The flexiVent (SCIREQ Scientific Respiratory Equipment; Montréal, Québec, Canada) was used to ventilate the lungs, deliver stepwise inspiratory and expiratory volume increments for the generation of PV curves, and superimpose sinusoidal forcing functions of multiple frequencies on the breathing frequency of the animal (2.5 Hz) for the determination of Z_RS.

Statistical Analyses of Data

The effect of genotype (wild‐type or IL-11Rα1‐deficient) and exposure (air or O₃) on body mass, PV curve parameters, and the majority of BAL analytes was assessed by a two-way analysis of variance (ANOVA) or by a Kruskal–Wallis one‐way ANOVA. Depending on the ANOVA utilized, the Fisher’s least significant difference (LSD) test or Wilcoxon rank-sum test were used for post hoc analyses. BAL IL-11 and the relative abundance of Il11ra1 mRNA were analyzed using a one‐way ANOVA. Pre- and postexposure body masses were compared using a Student’s t test for paired samples, whereas serum sTNFR 1 and sTNFR 2 were compared using a Student’s t test for npaired samples and a Wilcoxon rank-sum test, respectively. Statistical analyses of methacholine dose-response curves were performed using a mixed-model repeated measures three-way ANOVA (genotype × exposure × concentration of methacholine), whereas pairwise post hoc comparisons were calculated using Fisher’s LSD test. When necessary, data were transformed using the natural logarithm to meet the assumptions of the aforementioned statistical tests. Methacholine dose-response curves were analyzed using PROC MIXED in SAS (Version 9.4; SAS Institute, Inc.; Cary, NC), whereas all other data were analyzed using JMP 15 (SAS Institute, Inc.). Results are expressed as the means ± SE. A P < 0.05 was considered significant. Finally, different sample sizes for the various experiments in this study were due to power requirements.

RESULTS

Effect of O₃ on the Relative Abundance of Lung Il11ra1 mRNA in Wild-Type Mice

To ascertain whether O₃ altered the relative abundance of lung Il11ra1 mRNA in wild-type C57BL/6J mice 4 and/or 24 h after cessation of exposure, we employed RT-qPCR. As illustrated in Fig. 2A, O₃ had no effect on the abundance of lung Il11ra1 mRNA when expressed relative to lung Il11ra1 mRNA from air‐exposed wild‐type mice.

Figure 2. — Relative abundance of interleukin 11 receptor, α chain 1 (*Il11ra1*) mRNA in the left lung lobe (A) or concentration of bronchoalveolar lavage interleukin (IL)-11 (B) obtained from wild-type C57BL/6J mice 4 or 24 h after cessation of a 3-h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). The abundance of *Il11ra1* mRNA in O₃-exposed mice was expressed relative to *Il11ra1* mRNA in the left lung lobe of wild-type C57BL/6J mice 4 or 24 h after cessation of a 3-h exposure to air. In A, all data were normalized to the abundance of hypoxanthine guanine phosphoribosyl transferase mRNA. The data in A and B were analyzed via a one-way analysis of variance. Each value is expressed as the means ± SE. n = 4 or 5 mice in each group for A and n = 8 mice in each group for B.

Effect of O₃ on BAL and Serum IL-11 in Wild-Type Mice

IL-11 was detectable in BAL obtained from air- or O₃-exposed wild-type mice (Fig. 2B). However, regardless of the time interval examined, there was no statistically significant difference in BAL IL-11 between air- or O₃-exposed wild-type mice. Finally, consistent with results from healthy adult humans (67), IL-11 was undetectable in serum of wild-type mice irrespective of exposure (data not shown).

Effect of IL-11Rα1 Deficiency and O₃ on Inspiratory Capacity and Quasi-Static PV Relationships of the Respiratory System

In the absence of any inciting stimulus, overexpression of IL11 mRNA in a lung-specific fashion in mice increases lung volume and alters the quasi-static PV relationships of the lungs (68). Thus, it is plausible that deficiency of Il11ra1 may impact lung volumes or capacities in addition to the quasi-static PV relationships of the respiratory system in IL-11Rα1-deficient mice.

To that end, we measured A, an estimate of inspiratory capacity, and parameters describing the quasi-static PV relationships of the respiratory system (Area/A, K, and C_stat). A, Area/A, K, and C_stat were not different between air-exposed wild-type and IL-11Rα1-deficient mice (Fig. 3). In addition, O₃ had no effect on any of these indices in either genotype. Finally, there were no genotype-related differences in A, Area/A, K, or C_stat after O₃ exposure.

Figure 3. — A, an estimate of inspiratory capacity (A), area (hysteresis) of pressure-volume (PV) curves normalized for A (B), K, the parameter from the Salazar–Knowles equation reflecting the curvature of the upper portion of the expiratory limb of the PV curve (C), and C_stat, static compliance of the respiratory system (D). These indices were obtained from PV curves generated from wild-type C57BL/6J mice and mice genetically deficient in the gene encoding *Il11ra1* (IL-11Rα1-deficient mice) 24 h after cessation of a 3‐h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). Data were analyzed via a two-way analysis of variance, and pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. Each value is expressed as the means ± SE. For air-exposed mice, n = 8–10, whereas for O₃-exposed mice, n = 4.

Effect of IL-11Rα1 Deficiency and O₃ on Airway Responsiveness to Methacholine

Before and after exposure to air, wild-type mice weighed significantly more than IL-11Rα1-deficient mice (Table 1). Furthermore, when including the time from when the O₃ exposure commenced until the time the mice were anesthetized 24 h after cessation of exposure, body masses of wild-type and IL-11Rα1-deficient mice decreased, on average, by 12.7% (Table 1).

Table 1.

Pre- and postexposure body masses and baseline airway and lung parenchymal oscillation mechanics for wild-type and IL-11Rα1-deficient mice exposed to filtered room air or ozone

Genotype (Exposure)	Body Mass, g		R_aw (cmH₂O/mL/s)	G (cmH₂O/mL)	H (cmH₂O/mL)
Genotype (Exposure)	Preexposure	Postexposure	R_aw (cmH₂O/mL/s)	G (cmH₂O/mL)	H (cmH₂O/mL)
Wild-type (Air)	29.5 ± 0.8†	29.5 ± 0.8†	0.34 ± 0.01	3.71 ± 0.09	24.22 ± 0.71
IL-11Rα1-deficient (Air)	26.8 ± 0.7	26.4 ± 0.8‡	0.33 ± 0.01	3.61 ± 0.12	23.59 ± 1.04
Wild-type (O₃)	28.3 ± 0.4	24.9 ± 0.4‡§	0.35 ± 0.01	4.51 ± 0.20*	26.32 ± 0.85
IL-11Rα1-deficient (O₃)	28.4 ± 0.7	24.6 ± 0.8‡	0.32 ± 0.01	4.41 ± 0.44^&	23.29 ± 1.52

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The results are expressed as the means ± SE. n = 11 or 12 mice in each group. Measurements of preexposure body mass were made immediately before exposure to air or O₃ (2 parts/million) for 3 h, whereas measurements of postexposure body mass were obtained for the same animals 24 h after cessation of a 3-h exposure to air or O₃. Measurements of baseline airway (R_aw) and lung parenchymal (G and H) oscillation mechanics were made after administration of 1× phosphate-buffered saline 24 h after cessation of a 3-h exposure to either air or O₃. The effect of genotype and exposure on body mass were analyzed via a two-way ANOVA, and pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. Pre- and postexposure body mass comparisons of mice with the same genotype and exposure were calculated using a Student’s t test for paired samples. †P < 0.05 compared with IL-11Rα1-deficient mice with an identical exposure within respective pre- or postexposure column. ‡P < 0.05 compared with preexposure body mass. §P < 0.05 compared with wild-type mice exposed to air within postexposure column. *P < 0.05 compared with wild-type mice exposed to air. &P < 0.05 compared with IL-11Rα1-deficient mice exposed to air. air, filtered room air; G, coefficient of lung tissue damping; H, coefficient of lung tissue elastance; IL-11Rα1, interleukin-11 receptor subunit α-1; O₃, ozone; R_aw, airway resistance.

No differences in baseline R_aw, G, or H existed between air-exposed wild-type and IL-11Rα1-deficient mice (Table 1). Compared with genotype-matched, air-exposed controls, exposure to O₃ significantly increased baseline G but had no effect on baseline R_aw or H. Furthermore, no genotype-related differences in R_aw, G, or H existed after O₃ exposure.

Administration of aerosolized methacholine to wild-type and IL-11Rα1-deficient mice significantly increased R_aw, G, and H regardless of exposure (Fig. 4). There were no genotype-related differences in responses to methacholine for R_aw, G, or H after air exposure. As compared with genotype-matched, air-exposed controls, responses to methacholine for R_aw, G, and H were significantly increased by O₃ at several doses of methacholine. However, after O₃ exposure, responses to methacholine for R_aw and H were significantly attenuated in IL-11Rα1-deficient as compared with wild-type mice (Fig. 4, A and C). Specifically, responses to methacholine for R_aw and H were lower in O₃-exposed IL-11Rα1-deficient as compared with wild-type mice after administration of 10 and 30 mg/mL and 0.1, 1, 10, 30, and 100 mg/mL of methacholine, respectively.

Figure 4. — Responses to aerosolized acetyl-β-methylcholine chloride (methacholine) for (A) airway resistance (R_aw), (B) the coefficient of lung tissue damping (G), and (C) the coefficient of lung tissue elastance (H) in wild-type C57BL/6J mice and mice genetically deficient in the gene encoding *Il11ra1* (IL-11Rα1-deficient mice) 24 h after cessation of a 3-h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). Dose-response curves were analyzed via a mixed-model repeated measures three-way analysis of variance, whereas pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. Each value is expressed as the means ± SE. n = 11 or 12 mice for each group. *P < 0.05 compared with wild-type mice exposed to air. &Significant difference (P < 0.05) in responses to methacholine at the designated concentrations between air- and O₃-exposed IL-11Rα1-deficient mice. #P < 0.05 compared with IL-11Rα1-deficient mice exposed to O₃.

Effect of IL-11Rα1 Deficiency and O₃ on Lung Injury and Lung Inflammation

O₃-induced AHR is mechanistically coupled to select phenomena emblematic of O₃-induced lung injury and lung inflammation (49, 50, 54, 69–71), and IL-11 or IL-11Rα1 influences the severity of lung injury and lung inflammation in response to a number of insalubrious stimuli (16, 72–74). Thus, to determine if differences in airway responsiveness between O₃-exposed wild-type and IL-11Rα1-deficient mice are a result of genotype-related differences in the severity of O₃-induced lung injury and lung inflammation, we measured representative indices of these phenomena.

O₃-induced lung injury was assessed by surveying 1) lung hyperpermeability via quantification of BAL protein and 2) airway epithelial cell desquamation via enumeration of BAL ciliated epithelial cells (75, 76). After exposure to air, no genotype-related differences in BAL protein existed (Fig. 5A). As compared with genotype-matched, air-exposed controls, O₃ significantly increased BAL protein in wild-type and IL-11Rα1-deficient mice regardless of whether BAL was performed on the animals 4 or 24 h after cessation of exposure. Nevertheless, no genotype-related differences in BAL protein were extant between O₃-exposed wild-type and IL-11Rα1-deficient mice at either time interval. Similar results were obtained for BAL ciliated epithelial cells (Fig. 5B).

Figure 5. — Concentration of bronchoalveolar lavage (BAL) protein (A) and number of BAL ciliated epithelial cells (B) obtained from wild-type C57BL/6J and mice genetically deficient in the gene encoding *Il11ra1* (IL-11Rα1-deficient mice) 4 or 24 h after cessation of a 3-h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). BAL protein data were analyzed via a Kruskal–Wallis one-way analysis of variance (ANOVA), whereas pairwise post hoc comparisons were calculated using a Wilcoxon rank-sum test. BAL ciliated epithelial cells data were analyzed via a two-way analysis of variance, whereas pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. Each value is expressed as the means ± SE. n = 8 mice for each group. *P < 0.05 compared with wild-type mice exposed to air. &P < 0.05 compared with IL-11Rα1-deficient mice exposed to air.

To assess O₃-induced lung inflammation, we quantified select indices [BAL cytokines (adiponectin, hyaluronan, IL-6, KC, MIP-3α, and osteopontin) and BAL leukocytes (macrophages and neutrophils)] that contribute to O₃-induced lung pathology (49–54, 70, 77–79). Except for adiponectin and KC, which were significantly lower in IL-11Rα1-deficient compared with wild-type mice, no other genotype-related differences in any indices existed after exposure to air (Fig. 6). In wild-type and IL-11Rα1-deficient mice, BAL adiponectin, hyaluronan, IL-6, KC, MIP-3α, and neutrophils were significantly greater, whereas BAL macrophages were significantly lower compared with genotype-matched air-exposed controls 4 h after cessation of exposure to O₃. Twenty-four hours after the O₃ exposure ceased, BAL adiponectin, hyaluronan, KC, MIP-3α, osteopontin, and neutrophils were significantly greater in O₃-exposed wild-type and IL-11Rα-deficient mice compared with genotype-matched air-exposed controls. However, at 4 or 24 h after cessation of exposure to O₃, BAL adiponectin was significantly decreased in IL-11Rα1-deficient compared with wild-type mice, whereas BAL macrophages were significantly greater in O₃-exposed IL-11Rα1-deficient as compared with wild-type mice 24 h after cessation of exposure (Fig. 6, A and G). Finally, regardless of genotype or exposure, eosinophils and lymphocytes were rarely observed in BAL fluid (data not shown).

Figure 6. — Concentration of bronchoalveolar lavage (BAL; A) adiponectin, (B) hyaluronan, (C) interleukin (IL)-6, (D) keratinocyte chemoattractant (KC), (E) macrophage inflammatory protein (MIP)-3α, and (F) osteopontin in addition to the number of BAL (G) macrophages and (H) neutrophils obtained from wild-type C57BL/6J mice and mice genetically deficient in the gene encoding *Il11ra1* (IL-11Rα1-deficient mice) 4 or 24 h after cessation of a 3-h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). BAL adiponectin, KC, osteopontin, and macrophage data were analyzed via a two-way analysis of variance, whereas pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. BAL hyaluronan, IL-6, MIP-3α, and neutrophil data were analyzed via a Kruskal–Wallis one-way ANOVA, whereas pairwise post hoc comparisons were calculated using a Wilcoxon rank-sum test. Each value is expressed as the means ± SE. n = 7 or 8 mice for each group. *P < 0.05 compared with wild-type mice exposed to air. &P < 0.05 compared with IL-11Rα1-deficient mice exposed to air. #P < 0.05 compared with IL-11Rα1-deficient mice exposed to O₃.

Engagement of TNF-α with either of its single-pass transmembrane receptors, TNF receptor (TNFR) 1 or 2, initiates a myriad of intracellular signaling cascades (80). In addition, both TNFR 1 and 2 are essential for the manifestation of O₃-induced AHR (81, 82), and the soluble forms of TNFR 1 and 2, sTNFR 1 and sTNFR 2, respectively, can interfere with the binding of TNF to TNFR 1 or TNFR 2 on the cell surface (80). Furthermore, the administration of recombinant human IL-11 to patients with hematological malignancies increases serum sTNFR 1 (83). Consequently, if IL-11 alters sTNFR 1 or 2 expression, this could potentially impact the development of O₃-induced AHR. To that end, we quantified BAL sTNFR 1 and 2. There were no genotype-related differences in BAL sTNFR 1 or 2 in air-exposed mice (Fig. 7). As compared with genotype-matched, air-exposed controls, exposure to O₃ significantly increased BAL sTNFR 1 in wild-type and IL-11Rα1-deficient mice 4 or 24 h after cessation of exposure, whereas BAL sTNFR 2 was only increased at the 24-h time interval. In addition, there were no differences in serum sTNFR 1 (1.7 ± 0.2 vs. 1.9 ± 0.2 ng/mL) or sTNFR 2 (5.9 ± 0.5 vs. 6.4 ± 0.6 ng/mL) in air-exposed wild-type and IL-11Rα1-deficient mice, respectively. Thus, it is improbable that sTNFR 1 or 2 contribute to genotype-related differences in O₃-induced AHR (Fig. 4).

Figure 7. — Concentration of bronchoalveolar lavage (BAL; A) soluble tumor necrosis factor receptor (sTNFR) 1 and (B) sTNFR 2 obtained from wild-type C57BL/6J mice and mice genetically deficient in the gene encoding *Il11ra1* (IL-11Rα1-deficient mice) 4 or 24 h after cessation of a 3-h exposure to either filtered room air (air) or ozone (O₃; 2 parts/million). BAL sTNFR 1 data were analyzed via a two-way analysis of variance (ANOVA), whereas pairwise post hoc comparisons were calculated using Fisher’s least significance difference test. BAL sTNFR 2 data were analyzed via a Kruskal–Wallis one-way ANOVA, whereas pairwise post hoc comparisons were calculated using a Wilcoxon rank-sum test. Each value is expressed as the means ± SE. n = 8 mice for each group. *P < 0.05 compared with wild-type mice exposed to air. &P < 0.05 compared with IL-11Rα1-deficient mice exposed to air.

DISCUSSION

Administration of recombinant human IL-11 to wild-type mice via nasal insufflation causes AHR (42). Consistent with this observation, we demonstrate that IL-11Rα1, an indispensable receptor for IL-11 signal transduction (12), is required for maximal airway responsiveness to methacholine after acute inhalation exposure to O₃ (Fig. 4). Decreases in airway responsiveness in IL-11Rα1-deficient mice after O₃ exposure were not associated with concomitant decreases in BAL hyaluronan, KC, osteopontin, or neutrophils (Fig. 6), each of which contributes to the development of O₃-induced AHR (49, 50, 53, 70, 77).

IL-11Rα1 is expressed in multitudinous organs, including the brain, heart, liver, lung, kidney, spleen, and thymus (34), and we confirm this observation, in part, by demonstrating Il11ra1 mRNA is present in the lungs of wild-type C57BL/6J mice exposed to either air or O₃ (Fig. 2A). However, O₃ did not alter the relative abundance of Il11ra1 mRNA in wild-type mice at either 4 or 24 h after cessation of exposure. Il11ra1 mRNA expression has rarely been quantified in animal models of lung disease, and when it has been, the results are conflicting. For example, Cardó-Vila et al. (84) reported that Il11ra1 mRNA expression is upregulated in cancerous lung tissue of mice, whereas Traber et al. (72) demonstrated that Il11ra1 mRNA is unchanged in mouse lung tissue in the 24-h period after intratracheal instillation of Escherichia coli. In contrast, IL-11 protein levels or Il11 mRNA have been quantified in animal lungs by numerous investigators in the presence or absence of experimental lung disease. Lung IL-11 protein and/or Il11 mRNA expression is increased in rodent models of asthma, idiopathic pulmonary fibrosis, immune complex disease, and infection with Mycobacterium tuberculosis (85–88). However, BAL IL-11 was unaffected by exposure to 100% oxygen for 72 h (89). Consistent with this latter observation, we report that BAL IL-11 is unchanged by inhalation of O₃ (Fig. 2B), which analogously causes oxidant-induced lung injury. Nevertheless, we cannot rule out the possibility that IL-11 levels in the lung lining fluid were affected by O₃ exposure at time points other than 4 or 24 h after cessation of exposure. We can conclude, however, that the ability of IL-11Rα1 to contribute to AHR in wild-type mice 24 h after cessation of O₃ exposure does not require lung Il11ra1 mRNA expression or BAL IL-11 protein levels to be concomitantly altered.

In wild-type and IL-11Rα1-deficient mice, O₃ significantly increased responsiveness to methacholine for R_aw, G, and H (Fig. 4). However, O₃-induced increases in these indices were significantly attenuated in IL-11Rα1-deficient as compared with wild-type mice. Among responses to methacholine for R_aw, G, and H, differences in H were the most pronounced between O₃-exposed wild-type and IL-11Rα1-deficient mice (Fig. 4C). Increases in H after O₃ exposure result from enhanced closure of small airways, which may be a consequence of decreased surfactant activity and/or greater airway constriction (90, 91). O₃ deactivates lung surfactant, a phenomenon that causes small airway closure, and thus, increases H (90, 92). Because IL-11 increases surfactant expression (93), the loss of IL-11 signaling in IL-11Rα1-deficient mice would theoretically decrease surfactant expression, increase surface tension in the lung, enhance small airway closure, and subsequently cause greater increases in H in IL-11Rα1-deficient as compared with wild-type mice. However, we observed the exact opposite: IL-11Rα1-deficient mice exhibited decreased responsiveness to methacholine for H. Nevertheless, airway constriction was significantly decreased in IL-11Rα1-deficient as compared with wild-type mice after O₃ exposure (Fig. 4A). Therefore, diminished airway constriction in IL-11Rα1-deficient mice may be the reason responsiveness to methacholine for H was attenuated in these animals.

The lung epithelium is a physical barrier that limits diffusion of inhaled, injurious entities (e.g., antigens, microbes, and ultrafine particles) to the subepithelium (94). O₃ causes desquamation of the airway epithelium and lung hyperpermeability (61), phenomena that would theoretically increase access of inhaled methacholine to the airway smooth muscle and increase airway responsiveness. However, we found no genotype-related differences in O₃-induced increases in BAL protein or in the number of BAL ciliated epithelial cells (Fig. 5), which are indices of lung permeability and epithelial desquamation, respectively. Thus, it is improbable that differences in the availability of methacholine to the airway smooth muscle account for genotype-related differences in airway responsiveness, especially for R_aw.

Two signaling elements downstream of IL-11Rα1 could influence the development of O₃-induced AHR. First, classic IL-11 signaling requires formation of a heterohexameric complex that consists of two molecules of IL-11, IL-11Rα1, and gp130, and once formed, this complex results in the activation of STAT proteins, including STAT3 (2, 95, 96). STAT3 expressed in airway epithelial cells is required for the development of antigen-induced AHR (97). Therefore, it is conceivable that diminished airway responsiveness in O₃-exposed IL-11Rα1-deficient mice results from the loss of STAT3 activation initiated via engagement of IL-11 with IL-11Rα1. However, if abatement of STAT3 activation is the cause of decreased airway responsiveness in O₃-exposed IL-11Rα1-deficient mice, insufficient STAT3 activation in airway smooth muscle is an improbable cause for this phenomenon since IL-11-induced STAT3 activation is virtually nonexistent in airway smooth muscle cells (28). Second, IL-11 elicits phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (96, 98), and impeding ERK 1/2 activation via U0126, a mitogen-activated protein kinase kinase (MEK) inhibitor, reduces antigen-induced AHR (99). Thus, diminished activation of these aforementioned elements within the IL-11, IL-11Rα1, and gp130 signal transduction cascade (i.e., STAT3 AND ERK 1/2) could potentially reduce airway responsiveness in IL-11Rα1-deficient mice after exposure to O₃. However, we have also considered that differences in airway responsiveness between O₃-exposed IL-11Rα1-deficient and wild-type mice are a result of differences in expression of proinflammatory cytokines.

We and others have demonstrated that O₃-induced AHR is mechanistically coupled to several moieties associated with O₃-induced lung inflammation, including adiponectin, hyaluronan, KC, neutrophils, and osteopontin (49, 50, 52–54, 70). We found no differences in BAL hyaluronan, KC, osteopontin, or neutrophils between IL-11Rα1-deficient and wild-type mice after O₃ exposure, (Fig. 6, B, D, F, and H), which suggests that neither these cytokines nor neutrophils can account for the genotype-related differences in O₃-induced AHR. O₃ increased BAL adiponectin in both wild-type and IL-11Rα-deficient mice (Fig. 6A). However, BAL adiponectin was significantly decreased in IL-11Rα1-deficient as compared with wild-type mice after O₃ exposure. We previously reported that O₃-induced AHR was attenuated in mice genetically deficient in adiponectin, a hormone exclusively produced by adipocytes (100), and the locus of this attenuation was the lung parenchyma, which is represented by G and H, and not the central airways, which is represented by R_aw (54). Thus, in IL-11Rα1-deficient mice, it is conceivable that reductions in BAL adiponectin, in addition to diminished airway constriction, could account for the significant reduction in methacholine responsiveness for H in these animals after O₃ exposure.

IL-11 was originally designated as adipogenesis inhibitory factor because of its capacity to inhibit the differentiation of preadipocytes to adipocytes. However, adiponectin promotes adipogenesis (101, 102) and is produced exclusively in adipocytes and secreted into the circulation (100). Thus, adiponectin found in the epithelial lining fluid of the lung is derived from blood, and our previous data demonstrate that transport of adiponectin from blood to the lungs is facilitated by T-cadherin, an adiponectin binding protein (54). As demonstrated in Fig. 6A, BAL adiponectin was significantly lower in air- or O₃-exposed IL-11Rα1-deficient as compared with wild-type mice, and there are two scenarios we have considered to explain this observation. First, in adipocyte-like cells, IL-11 induces phosphorylation of ribosomal protein S6 kinase β-1, also known as p70 S6K (96), which is required for induction of adiponectin expression in white adipose tissue (103). Thus, the loss of p70 S6K phosphorylation in IL-11Rα1-deficient mice could decrease adiponectin expression in adipose tissue, and consequently reduce the amount of adiponectin released into the circulation. Second, it is conceivable that BAL adiponectin levels are decreased in IL-11Rα1-deficient mice because IL-11Rα1 contributes to the transport of adiponectin from blood to the epithelial lining fluid of the lung via regulating T-cadherin expression. Nevertheless, our data do not allow us to distinguish if either of these scenarios is true. Regardless of the precise mechanism, this is the first study to demonstrate that IL-11Rα1 regulates in vivo expression of adiponectin and/or its transit from blood to the epithelial lining fluid of the lung. Finally, because 1) IL-11Rα1 and IL-11 influence expression of adiponectin and leptin, respectively [Fig. 6A and (104)], 2) expression of these hormones in visceral adipose tissue is significantly different between obese asthmatics and obese nonasthmatics (105), and 3) visceral adipose tissue leptin expression is significantly related to AHR (105), it is reasonable to speculate that IL-11 could contribute in some manner to the natural history of obesity-induced asthma.

We previously reported that BAL protein, IL-6, KC, and neutrophils were significantly lower in adiponectin-deficient as compared with wild-type mice after cessation of a 3-h exposure to O₃ (2 ppm) (54). However, in this study, despite observing significantly less BAL adiponectin in IL-11Rα1-deficient mice, we observed no genotype-related differences in any of the aforementioned indices 4 or 24 h after cessation of O₃ exposure (Figs. 5A and 6, A, D, and H). These data suggest that BAL adiponectin must be decreased to a greater extent or completely absent to significantly impact the development of O₃-induced lung inflammation.

Since 1) overexpression of IL11 mRNA in a lung-specific fashion in mice decreases BAL neutrophils in response to oxygen toxicity, 2) administration of a neutralizing antibody against IL-11 reduces neutrophil migration to the air spaces in a mouse model of Escherichia coli pneumonia, and 3) deficiency of IL-11Rα1 decreases BAL eosinophils and IL-13 in antigen sensitized and challenged mice (16, 72, 73), we were surprised that IL-11Rα1 deficiency had only minimal effects on O₃-induced lung inflammation (i.e., BAL adiponectin and macrophages). The three aforementioned observations suggest that the contribution of IL-11 and/or IL-11Rα1 to inflammatory responses is stimulus-specific, analogous to IL-6 (51, 106, 107). Alternatively, Kleeberger et al. (108) reported that separate genetic loci control the appearance of polymorphonuclear leukocytes in BAL fluid after acute (2 ppm for 3 h) and subacute (0.3 ppm for 48 h) exposure to O₃, and in support of this work, we previously demonstrated that IL-6 and the type I IL-1 receptor minimally contribute to O₃-induced lung inflammation after acute O₃ exposure (2 ppm for 3 h) but profoundly influence the development of lung inflammation after subacute O₃ exposure (0.3 ppm for 72 h) (51, 109). Thus, because IL-6 and IL-11 belong to the same cytokine family (29), it is plausible that IL-11 and/or IL-11Rα1 contribute more extensively to O₃-induced lung inflammation after subacute exposure. Furthermore, Smith et al. (110) recently demonstrated that mice from the Collaborative Cross exposed to 0.8 ppm O₃ for 4 h per day for 9 days exhibited eosinophilic lung inflammation, airway mucous cell metaplasia, and AHR. Given that IL-11Rα1 deficiency lessens the severity of O₃-induced AHR (Fig. 4) and given that IL-11Rα1 deficiency reduces BAL eosinophils and mucus in antigen-sensitized and challenged mice (16), it is not unreasonable to speculate that IL-11Rα1 deficiency could reduce all of the aforementioned pathological features induced by repeated exposure to O₃ described by Smith et al. (110).

As a criteria pollutant, the United States Environmental Protection Agency is required to establish primary and secondary National Ambient Air Quality Standards for O₃, and as of 2020, both standards are 0.070 ppm (111, 112). However, in this study, mice were exposed to a concentration of O₃ (2 ppm) whose environmental or occupational existence is quite inconceivable. In laboratory experiments assessing the respiratory effects of O₃ on human subjects, participants are moderately or strenuously exercising while exposed to O₃ concentrations significantly less (0.12−0.4 ppm) than 2 ppm (113–115). Since exercise increases minute ventilation (V̇_e) and since the dose of O₃ delivered to the lungs is the product of O₃ concentration, exposure time, and V̇_e (116), exercising humans inhale a greater dose of O₃ than their resting counterparts. In contrast to humans, wild-type C57BL/6J mice exhibit prolonged sedentariness and profound decreases in V̇_e during exposure to O₃ (82). Consequently, based on differences in V̇_e among these species during O₃ exposure, the dose of O₃ delivered to the lungs is presumably different when humans and mice are exposed to the same O₃ concentration for the same length of time. Consistent with this hypothesis, Hatch et al. (115) reported that the dose of O₃ delivered to the lungs of exercising humans and sedentary rodents is dissimilar when exposed to O₃ (0.4 ppm) for 2 h. In fact, for humans and rodents to exhibit equivalent degrees of O₃-induced lung pathology, Hatch et al. (115) demonstrated that rodents must be exposed to an O₃ concentration five times greater than humans (2 ppm as compared with 0.4 ppm, respectively). Therefore, in this study, we exposed mice to 2 ppm O₃ because it causes a similar degree of lung injury and lung inflammation in human subjects exposed to lower and more environmentally relevant concentrations of O₃.

PERSPECTIVES AND SIGNIFICANCE

In conclusion, we demonstrate that BAL adiponectin and increases in airway responsiveness to methacholine are significantly attenuated in IL-11Rα1-deficient as compared with wild-type mice after acute inhalation exposure to O₃. Since adiponectin contributes to the development of O₃-induced AHR (54), decreases in BAL adiponectin in IL-11Rα1-deficient mice could be mechanistically coupled to the attenuation of O₃-induced AHR in these animals. Regardless of the role of adiponectin, this is the first study to demonstrate that IL-11Rα1 is essential for maximal increases in airway responsiveness to methacholine after exposure to O₃, a nonatopic asthma stimulus.

DATA AVAILABILITY

Raw data used to calculate means and standard errors of the means presented in Table 1, Figs. 2–7, and the text are publicly available on the NIOSH Data and Statistics Gateway under Data set Number RD-1047–2022-0.

GRANTS

The research reported in this publication was supported, in part, by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Nos. R03ES022378 (to R.A.J.) and R03ES024883 (to R.A.J.) and by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award No. R03AI107432 (to R.A.J.).

DISCLOSURES

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention. Furthermore, the content contained within this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

AUTHOR CONTRIBUTIONS

R.A.J. and I.U.H. conceived and designed research; R.A.J., C.L.A., S.R.S., W.T.J., N.C.M., C.Y.S., and A.W.P.4th. performed experiments; R.A.J., S.R.S., W.T.J., N.C.M., A.W.P.4th., and M.L.K. analyzed data; R.A.J. and M.L.K. interpreted results of experiments; R.A.J. and A.W.P.4th. prepared figures; R.A.J. drafted manuscript; R.A.J., C.L.A., S.R.S., W.T.J., N.C.M., C.Y.S., A.W.P.4th., M.L.K., and I.U.H. edited and revised manuscript; R.A.J., C.L.A., S.R.S., W.T.J., N.C.M., C.Y.S., A.W.P.4th., M.L.K., and I.U.H. approved final version of manuscript.

ACKNOWLEDGMENTS

The authors thank Dr. Brendan J. Jenkins (Hudson Institute of Medical Research; Clayton, Victoria, Australia) and Dr. Trevelyan R. Menheniott (Murdoch Children’s Research Institute; Parkville, Victoria, Australia) for providing us with genotyping protocols for IL-11Rα1-deficient mice.

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Data Availability Statement

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PERMALINK

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone

Richard A Johnston

Constance L Atkins

Saad R Siddiqui

William T Jackson

Nicholas C Mitchell

Chantal Y Spencer

Albert W Pilkington 4th

Michael L Kashon

Ikram U Haque

Abstract

INTRODUCTION

MATERIALS AND METHODS

Animals

Figure 1.

Protocol

Air and O3 Exposures

Blood Collection, BAL, and Lung Harvest

RNA Extraction, cDNA Synthesis, and Reverse Transcription-Quantitative Real-Time Polymerase Chain Reaction

Cytokine and Protein Quantification

Quasi-Static Respiratory System PV Curves and Airway Responsiveness to Methacholine

Statistical Analyses of Data

RESULTS

Effect of O3 on the Relative Abundance of Lung Il11ra1 mRNA in Wild-Type Mice

Figure 2.

Effect of O3 on BAL and Serum IL-11 in Wild-Type Mice

Effect of IL-11Rα1 Deficiency and O3 on Inspiratory Capacity and Quasi-Static PV Relationships of the Respiratory System

Figure 3.

Effect of IL-11Rα1 Deficiency and O3 on Airway Responsiveness to Methacholine

Table 1.

Figure 4.

Effect of IL-11Rα1 Deficiency and O3 on Lung Injury and Lung Inflammation

Figure 5.

Figure 6.

Figure 7.

DISCUSSION

PERSPECTIVES AND SIGNIFICANCE

DATA AVAILABILITY

GRANTS

DISCLOSURES

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Air and O₃ Exposures

Effect of O₃ on the Relative Abundance of Lung Il11ra1 mRNA in Wild-Type Mice

Effect of O₃ on BAL and Serum IL-11 in Wild-Type Mice

Effect of IL-11Rα1 Deficiency and O₃ on Inspiratory Capacity and Quasi-Static PV Relationships of the Respiratory System

Effect of IL-11Rα1 Deficiency and O₃ on Airway Responsiveness to Methacholine

Effect of IL-11Rα1 Deficiency and O₃ on Lung Injury and Lung Inflammation