IL-1α/IL-1R1 Expression in Chronic Obstructive Pulmonary Disease and Mechanistic Relevance to Smoke-Induced Neutrophilia in Mice Academic Article uri icon

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abstract

  • BACKGROUND: Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood. METHODOLOGY AND PRINCIPAL FINDINGS: The objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation. CONCLUSIONS AND SIGNIFICANCE: This study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.

authors

  • Stampfli, Martin R
  • Botelho, Fernando M
  • Bauer, Carla MT
  • Finch, Donna
  • Nikota, Jake K
  • Zavitz, Cale
  • Kelly, Ashling
  • Lambert, Kristen N
  • Piper, Sian
  • Foster, Martyn L
  • Goldring, James JP
  • Wedzicha, Jadwiga A
  • Bassett, Jennifer
  • Bramson, Jonathan
  • Iwakura, Yoichiro
  • Sleeman, Matthew
  • Kolbeck, Roland
  • Coyle, Anthony J
  • Humbles, Alison A
  • Stämpfli, Martin R

publication date

  • 2011