Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.

Autor: Portelli MA; Centre for Respiratory Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK., Ketelaar ME; Groningen Research Institute for Asthma and COPD, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; Groningen Research Institute for Asthma and COPD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Bates S; UK Respiratory Therapeutic Unit, GlaxoSmithKline pPlc, 1929, Brentford, UK., Csomor E; UK Respiratory Therapeutic Unit, GlaxoSmithKline pPlc, 1929, Brentford, UK., Shaw D; Centre for Respiratory Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK., Emsley J; School of Pharmacy, Biodiscovery Institute, University of Nottingham, Nottingham, UK., Brightling C; Respiratory Sciences, Glenfield Hospital, University of Leicester, Leicester, UK., Hall I; Centre for Respiratory Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK., Affleck K; Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK., Edwards M; UK Respiratory Therapeutic Unit, GlaxoSmithKline pPlc, 1929, Brentford, UK., Nawijn MC; Groningen Research Institute for Asthma and COPD, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; Groningen Research Institute for Asthma and COPD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Koppelman GH; Groningen Research Institute for Asthma and COPD, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Van Oosterhout AJ; Allergic Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK., Sayers I; Centre for Respiratory Research, National Institute for Health Research Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK.
Jazyk: angličtina
Zdroj: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology [Clin Exp Allergy] 2024 Sep 20. Date of Electronic Publication: 2024 Sep 20.
DOI: 10.1111/cea.14562
Abstrakt: Introduction: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway.
Method: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33 112-270 (50 ng/mL) and induced IL-8 mRNA expression measured.
Results: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL33 95-270 and IL33 106-270 had the greatest effect and the IL33 113-270 , and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes.
Conclusions: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL33 95-270 and IL33 106-270 may be more amenable to IL33/IL1RL1 targeting.
(© 2024 The Author(s). Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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