Melody G. Duvall1,2, 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. Levy1,*,†, National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 InvestigatorsScience Immunology 10 Mar 2017: Vol. 2, Issue 9, DOI: 10.1126/sciimmunol.aam5446
Natural killer cell–mediated inflammation resolution is disabled in severe asthma
- Published on Saturday, 11 March 2017 12:04
- Written by Juan Carlos Ivancevich
NK cells in severe asthma—Failed resolution
Anti-inflammatory corticosteroids are a first line of defense against many types of asthma, but patients with severe asthma do not frequently respond to this therapy. Duvall et al. now report that this lack of response may be due in part to defects in natural killer (NK) cells, which are important mediators of inflammation resolution. They found that NK cells from patients with severe asthma had impaired killing and that corticosteroid exposure further inhibited the function of these cells, whereas the proresolving mediator LXA4 preserved NK cell effector mechanisms. Therefore, corticosteroids may be a counterproductive therapy in patients with severe asthma, and specifically activating NK cells may provide an alternate therapeutic target.
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 CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim 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.