Natural killer cell-mediated inflammation resolution is disabled in severe asthma

Melody G Duvall; Cindy Barnig; Manuela Cernadas; Isabell Ricklefs; Nandini Krishnamoorthy; Nicole L Grossman; Nirav R Bhakta; John V Fahy; Eugene R Bleecker; Mario Castro; Serpil C Erzurum; Benjamin M Gaston; Nizar N Jarjour; David T Mauger; Sally E Wenzel; Suzy A Comhair; Andrea M Coverstone; Merritt L Fajt; Annette T Hastie; Mats W Johansson; Michael C Peters; Brenda R Phillips; Elliot Israel; Bruce D Levy; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators

doi:10.1126/sciimmunol.aam5446

Natural killer cell-mediated inflammation resolution is disabled in severe asthma

Sci Immunol. 2017 Mar 10;2(9):eaam5446. doi: 10.1126/sciimmunol.aam5446.

Authors

Melody G Duvall^{1

2}, Cindy Barnig³, Manuela Cernadas¹, Isabell Ricklefs¹, Nandini Krishnamoorthy¹, Nicole L Grossman¹, Nirav R Bhakta⁴, John V Fahy⁴, Eugene R Bleecker⁵, Mario Castro⁶, Serpil C Erzurum⁷, Benjamin M Gaston⁸, Nizar N Jarjour⁹, David T Mauger¹⁰, Sally E Wenzel¹¹, Suzy A Comhair⁷, Andrea M Coverstone¹², Merritt L Fajt¹¹, Annette T Hastie⁵, Mats W Johansson¹³, Michael C Peters⁴, Brenda R Phillips¹⁰, Elliot Israel¹, Bruce D Levy¹⁴; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators

Affiliations

¹ Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
² Division of Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Chest Diseases, University Hospital of Strasbourg, Strasbourg, France.
⁴ Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Center for Genomics and Personalized Medicine Research, School of Medicine, Wake Forest University, Winston-Salem, NC 27157, USA.
⁶ Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, Washington University, St. Louis, MO 63110, USA.
⁷ Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁸ Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH 44106, USA.
⁹ Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
¹⁰ Division of Statistics and Bioinformatics, Department of Public Health Sciences, Pennsylvania State University, Hershey, PA 17033, USA.
¹¹ Pulmonary, Allergy and Critical Care Medicine Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
¹² Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹³ Department of Biomolecular Chemistry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
¹⁴ Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. blevy@partners.org.

Abstract

Severe asthma is typically characterized by chronic airway inflammation that is refractory to corticosteroids and associated with excess morbidity. Patients were recruited into the National Heart, Lung, and Blood Institute-sponsored Severe Asthma Research Program and comprehensively phenotyped by bronchoscopy. Bronchoalveolar lavage (BAL) cells were analyzed by flow cytometry. Compared with healthy individuals (n = 21), patients with asthma (n = 53) had fewer BAL natural killer (NK) cells. Patients with severe asthma (n = 29) had a marked increase in the ratios of CD4⁺ T cells to NK cells and neutrophils to NK cells. BAL NK cells in severe asthma were skewed toward the cytotoxic CD56^dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56^dim NK cells and CCR6^-CCR4^- T helper 1-enriched CD4⁺ T cells correlated inversely with lung function [forced expiratory volume in 1 s (FEV₁) % predicted] in asthma. Relative to cells from healthy controls, peripheral blood NK cells from asthmatic patients had impaired killing of K562 myeloid target cells despite releasing more cytotoxic mediators. Ex vivo exposure to dexamethasone markedly decreased blood NK cell lysis of target cells and cytotoxic mediator release. NK cells expressed airway lipoxin A₄/formyl peptide receptor 2 receptors, and in contrast to dexamethasone, lipoxin A₄-exposed NK cells had preserved functional responses. Together, our findings indicate that the immunology of the severe asthma airway is characterized by decreased NK cell cytotoxicity with increased numbers of target leukocytes, which is exacerbated by corticosteroids that further disable NK cell function. These failed resolution mechanisms likely contribute to persistent airway inflammation in severe asthma.

Abstract

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