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<p>Interleukin-1β (IL-1β) is a key mediator of innate immunity and a central driver of airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). Elevated IL-1β levels in sputum, bronchoalveolar lavage, and airway tissues correlate with neutrophilic inflammation, exacerbation frequency, airflow limitation, and steroid resistance. Mechanistically, IL-1β promotes epithelial activation, epithelial–mesenchymal transition, neutrophil recruitment, inflammasome activation, and immune cell plasticity, particularly driving ILC2 transdifferentiation toward pro-inflammatory phenotypes. Despite strong biological rationale, clinical trials targeting IL-1 signaling through receptor blockade or IL-1β neutralization have yielded limited benefits in certain patient populations. Therapeutic failure is largely attributed to disease heterogeneity, lack of biomarker-guided stratification, redundant inflammatory pathways, and suboptimal timing of intervention. Emerging strategies include precision medicine approaches with biomarker enrichment, upstream NLRP3 inflammasome inhibition, combinatorial cytokine targeting, modulation of signaling intermediates, temporally targeted therapy during exacerbations, and localized airway delivery systems. Integration of multi-omics profiling and endotype-based patient selection may enhance therapeutic responsiveness. Future clinical trials should adopt adaptive designs to validate IL-1-targeted interventions in biologically defined subgroups of patients with asthma or COPD.</p>

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IL-1β Pathway Inhibition in Asthma and COPD: Strong Biological Rationale, Disappointing Clinical Trials, and Emerging New Opportunities

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

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  • Mario Cazzola,
  • Clive P. Page,
  • Maria Gabriella Matera

摘要

Interleukin-1β (IL-1β) is a key mediator of innate immunity and a central driver of airway inflammation in asthma and chronic obstructive pulmonary disease (COPD). Elevated IL-1β levels in sputum, bronchoalveolar lavage, and airway tissues correlate with neutrophilic inflammation, exacerbation frequency, airflow limitation, and steroid resistance. Mechanistically, IL-1β promotes epithelial activation, epithelial–mesenchymal transition, neutrophil recruitment, inflammasome activation, and immune cell plasticity, particularly driving ILC2 transdifferentiation toward pro-inflammatory phenotypes. Despite strong biological rationale, clinical trials targeting IL-1 signaling through receptor blockade or IL-1β neutralization have yielded limited benefits in certain patient populations. Therapeutic failure is largely attributed to disease heterogeneity, lack of biomarker-guided stratification, redundant inflammatory pathways, and suboptimal timing of intervention. Emerging strategies include precision medicine approaches with biomarker enrichment, upstream NLRP3 inflammasome inhibition, combinatorial cytokine targeting, modulation of signaling intermediates, temporally targeted therapy during exacerbations, and localized airway delivery systems. Integration of multi-omics profiling and endotype-based patient selection may enhance therapeutic responsiveness. Future clinical trials should adopt adaptive designs to validate IL-1-targeted interventions in biologically defined subgroups of patients with asthma or COPD.