Oncostatin‐M Is Produced by Human Eosinophils and Expression Is Increased in Uncontrolled Severe Asthma
Authors: Stephane Esnault, Ksenija Bernau, Heather L. Floerke, Arnaud Dendooven, Emeline Delaunay, Kimberly A. Dill‐McFarland, Matthew C. Altman, William W. Busse, Melissa A. Rosenkranz, Matthew C. Tattersall, Mats W. Johansson, Julien Labreuche, Delphine Beury, Shéhérazade Sebda, Frédéric Dezoteux, Baptiste Segard, Geoffrey Mortuaire, Delphine Staumont‐Sallé, Thomas Stoup, Cécile Chenivesse, Nathan Sandbo, Nizar N. Jarjour, Guillaume Lefèvre
Journal: Allergy (2024)

The development of airway remodeling in asthma is believed to be a consequence of airway inflammation, including eosinophilia, a hallmark of asthma and asthma severity. We previously found that eosinophil products activate fibroblasts, with IL-1, oncostatin-M (OSM) and TNFSF12 as predicted eosinophilic factors responsible for fibroblast activation [1]. OSM, a member of the gp130 ligand family of cytokines, is produced by immune cells, but it is typically not recognized as an eosinophilic product. OSM has been associated with asthma severity and lower lung function [2], and it was reported that OSM upregulates gene expression levels that may promote airway granulocytic inflammation and mucus production [2]. In nasal polyps (NP) of patients with chronic rhinosinusitis (CRS), tissue OSM correlates with epithelial dysfunction and TSLP expression, but the main source in tissue appears to be the neutrophil [3, 4]. In our present study, we asked whether human blood eosinophils are a source of OSM and analyzed associations between OSM and airway eosinophilia, lung function, and other mediators in asthma. Blood eosinophils from nine allergic participants were cultured with IL-3 for 20 h. Then, eosinophils were seeded on heat-aggregated IgG for 6 h, which is a well-known model to induce robust degranulation and cytolysis of blood eosinophils [5]. Figure 1A (left panel) shows that in absence of IgG, eosinophils spontaneously released low but detectable amounts of OSM (median [interquartile range; IQR] of 9 pg/mL [4.0, 15.5]) while on IgG (IL3IgG), OSM secretion was 5-fold higher (median IQR of 47 pg/mL [39.5, 55]). Using 3′UTR RNA-seq, we analyzed OSM mRNA expression level in blood eosinophils activated in vitro with IL-3 or eotaxin-1 for 6 h. We found that IL-3 increased OSM expression level (3.5-fold versus no activation) (Figure 1A; right panel). Next, to establish a relationship between airway eosinophilia and OSM in vivo in a type-2 human model, we measured the amount of OSM protein in bronchoalveolar lavage (BAL) fluids (BALF) before and 48 h after a segmental bronchoprovocation with an allergen (SBP-Ag) in 18 subjects with mild asthma (previously described in [6]). OSM was detectable in most BALF before SBP-Ag (median IQR of 31 pg/mL [31,45]) and OSM amount increased after the challenge (median IQR of 78 pg/mL [35.5,186.5], p < 0.0001). The change in BALF OSM concentration after challenge was correlated with the change in concentration of BALF eosinophils (Figure 1B) and was inversely correlated with the change in lung function as determined using FEV1 (%P) (r = −0.676, p = 0.002; Table S1). Moreover, to analyze OSM protein in BALF vis-à-vis other well-known mediators of the immune response, 92 mediators were measured in BALF prepared before and after SBP-Ag using Olink Proteomics technology. Changes in BALF OSM strongly correlated with changes in TSLP, Lap-TGF-b1, chemokines, and proinflammatory cytokines (Figure 1C). Furthermore, changes in paired blood OSM amount correlated with changes in BALF OSM (Figure 1D), suggesting an inside-out mechanism with potential systemic impact following SBP-Ag. In Figure 2, we examined whether blood eosinophils displayed higher expression of OSM gene in severe asthma (n = 21) compared to healthy individuals (n = 19) and patients suffering from CRSwNP (n = 18) (Figure 2A). After adjustment for sex, expression level of OSM in isolated blood eosinophils was significantly elevated in severe asthma versus control and CRSwNP (Figure 2B), and OSM levels tended to correlate with two markers for loss of asthma control (ACQ and exacerbations) (Figure 2C). In conclusion, OSM is a product from activated eosinophils, and its expression is enhanced in eosinophils from patients with uncontrolled severe asthma. Airway OSM levels are associated with poorer lung function and multiple markers of inflammation and remodeling. This study should encourage further investigations on the role of OSM in asthma with the prospect that OSM, its inducer(s) or its downstream signaling becomes a drug target to treat eosinophilic asthma. All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; and have been involved in drafting the manuscript or revising it critically for important intellectual content; and have given final approval of the version to be published. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content; and they agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. We thank the research participants from whom the data were acquired for their contributions to this work, the research nurse coordinators in the UW-Madison Clinical Core facility (P.I. Loren Denlinger) for subject recruitment and screening, and Paul Fichtinger for the preparation of blood eosinophils (P.I. Sameer Mathur). We thank Jean-Pascal Meneboo, Frédéric Leprêtre, and Martin Figeac (PLBS UAR 2014-US 41) for their implication in RNA-sequencing data processing. K. Bernau received funding from the Pulmonary Fibrosis Foundation, by an independent grant from Boehringer Ingelheim Pharmaceuticals Inc. who provided the financial support outside of the submitted work. W. W. Busse reports consulting fees/honoraria from GlaxoSmithKline, Regeneron, Sanofi, and Genentech, and royalties from Elsevier. N. N. Jarjour received research funding from AstraZeneca for extension of the National Institutes of Health–funded severe asthma research program; and received consulting fees over the past 3 years from GlaxoSmithKline, Chiese, and AstraZeneca related to asthma treatment. K. A. Dill-McFarland reports consulting fees from Seattle BioSoftware and EuropaDX related to computational tool development. F. Dezoteux was investigator for clinical trials sponsored by Abbvie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron; received consulting fees by AbbVie, Almirall, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, Sanofi-Regeneron, and UCB. D. Staumont-Sallé received funding from AstraZeneca for a research study in DRESS syndrome; was investigator for clinical trials sponsored by Abbvie, Almirall, Amgen, AstraZeneca, Eli Lilly, Galderma, Leo Pharma, Novartis, Pfizer, and Sanofi-Regeneron; received consulting fees by AbbVie, Almirall, AstraZeneca, Eli Lilly, Galderma, GSK, Leo Pharma, Novartis, Pfizer, Sanofi-Regeneron, and UCB. C. Chenivesse declares research grants from AstraZeneca, GlaxoSmithKlein, Santelys, and Novartis, personal fees from ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi, and GlaxoSmithKlein and congress support from AstraZeneca, Boehringer Ingelheim, Chiesi, and Novartis. G. Lefèvre received consulting fees, personal fees for advisory boards or meetings, and research fundings from AstraZeneca and GSK. These relationships with pharmaceutical companies are not relevant to the current study. M. W. Johansson received funding from Hoffmann-La Roche, outside of the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. All the data used in this manuscript are available to the public. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.