title: Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma.
abstract: BACKGROUND
  Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.
  
  
  METHODS
  Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.
  
  
  RESULTS
  Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.
  
  
  CONCLUSIONS
  We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Derek K
authors: DK
authors: Chu
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Amal
authors: A
authors: Al-Garawi
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Alba
authors: A
authors: Llop-Guevara
authors: Division of Pulmonary and Critical Care Medicine, and Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas USA.
authors: Regina A
authors: RA
authors: Pillai
authors: Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Katherine
authors: K
authors: Radford
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Pamela
authors: P
authors: Shen
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Tina D
authors: TD
authors: Walker
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Susanna
authors: S
authors: Goncharova
authors: Division of Pulmonary and Critical Care Medicine, and Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas USA.
authors: William J
authors: WJ
authors: Calhoun
authors: Division of Respirology, Department of Medicine, McMaster University, Hamilton, Ontario Canada.
authors: Parameswaran
authors: P
authors: Nair
authors: Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Hamilton, ON Canada.
authors: Manel
authors: M
authors: Jordana
keywords: Airway inflammation; Allergy; Asthma; Bronchitis; Eosinophil; Granulocyte; House dust-mite (HDM); IL-6; IL-6R; Neutrophil