ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Signaling
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1566482
IL-6 trans-signaling in cystic fibrosis bronchial cells potentiates TNF-a-driven ICAM-1 expression
Provisionally accepted
- 1Research Institute, McGill University Health Center, Montreal, Quebec, Canada
- 2McGill University, Montreal, Canada
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Pseudomonas aeruginosa is gram-negative bacillus that causes chronic airway infections, leading to severe pulmonary inflammation in cystic fibrosis. This bacterial infection is frequently associated with a massive recruitment of neutrophils and an abnormal increase in production of inflammatory cytokines. Among these cytokines, interleukin (IL)-6 has both anti-and pro-inflammatory properties able to signal through classic and trans-signaling pathways, respectively. Furthermore, IL-6 is known to be upregulated in CFTR-deficient bronchial cell lines in the presence of Pseudomonas aeruginosa-derived filtrates and in Pulmonary Exacerbations (PEx). In this study, we aimed to determine whether IL-6 trans-signaling could contribute to neutrophilic inflammation leading to lung tissue damage during PEx of people with CF (pwCF). Herein, we show that pwCF had higher sIL-6Rα levels in their plasma during PEx, suggestive of IL-6 trans-signaling. Furthermore, we show that a CF bronchial cell line is hyperresponsive to both classic and trans-signaling, with the higher levels of activation occurring during trans-signaling when compared to two non-CF cell lines. Our data unveiled that ICAM-1, which promotes neutrophil adhesion, is upregulated by the combination of TNFα and IL-6 signaling in CF bronchial cells. Interestingly, soluble IL-6R (sIL-6Rα) protects IL-6 from degradation by bacterial proteases. Therefore, we suggest that strategies which target IL-6 trans-signaling may alleviate ICAM-1 mediated neutrophil adhesion and reduce subsequent lung damage in PEx.
Keywords: inflammation, infection, epithelium, innate immunity, Cystic Fibrosis Pseudomonas aeruginosa, Cystic fibrosis transmembrane regulator, Cystic Fibrosis, Pulmonary exacerbations, Inflammation, IL-6 trans-signaling, ICAM-1
Received: 24 Jan 2025; Accepted: 18 Aug 2025.
Copyright: © 2025 Lin, Fourcade, Roussel, Marabella, Nguyen and Rousseau. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Simon Rousseau, McGill University, Montreal, Canada
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