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

National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 CD56dim subset, with significantly increased BAL fluid levels of the cytotoxic mediator granzyme A. The numbers of BAL CD56dim NK cells and CCR6CCR4 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.

Original languageEnglish (US)
Article numbereaam5446
JournalScience Immunology
Volume2
Issue number9
DOIs
StatePublished - Jan 1 2017

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Natural Killer Cells
Asthma
Inflammation
Bronchoalveolar Lavage
Dexamethasone
Blood Cells
Adrenal Cortex Hormones
Lipoxins
Formyl Peptide Receptor
T-Lymphocytes
Granzymes
Lung
Natural Killer T-Cells
K562 Cells
Bronchoalveolar Lavage Fluid
Forced Expiratory Volume
Bronchoscopy
Myeloid Cells
Allergy and Immunology
Leukocyte Count

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy

Cite this

National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators (2017). Natural killer cell–mediated inflammation resolution is disabled in severe asthma. Science Immunology, 2(9), [eaam5446]. https://doi.org/10.1126/sciimmunol.aam5446
National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. / Natural killer cell–mediated inflammation resolution is disabled in severe asthma. In: Science Immunology. 2017 ; Vol. 2, No. 9.
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title = "Natural killer cell–mediated inflammation resolution is disabled in severe asthma",
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 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.",
author = "{National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators} and Duvall, {Melody G.} and Cindy Barnig and Manuela Cernadas and Isabell Ricklefs and Nandini Krishnamoorthy and Grossman, {Nicole L.} and Bhakta, {Nirav R.} and Fahy, {John V.} and Bleecker, {Eugene R.} and Mario Castro and Erzurum, {Serpil C.} and Gaston, {Benjamin M.} and Jarjour, {Nizar N.} and Mauger, {David T.} and David Mauger and Comhair, {Suzy A.} and Coverstone, {Andrea M.} and Fajt, {Merritt L.} and Hastie, {Annette T.} and Johansson, {Mats W.} and Peters, {Michael C.} and Phillips, {Brenda R.} and Elliot Israel and Levy, {Bruce D.}",
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National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators 2017, 'Natural killer cell–mediated inflammation resolution is disabled in severe asthma', Science Immunology, vol. 2, no. 9, eaam5446. https://doi.org/10.1126/sciimmunol.aam5446

Natural killer cell–mediated inflammation resolution is disabled in severe asthma. / National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators.

In: Science Immunology, Vol. 2, No. 9, eaam5446, 01.01.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Natural killer cell–mediated inflammation resolution is disabled in severe asthma

AU - National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators

AU - Duvall, Melody G.

AU - Barnig, Cindy

AU - Cernadas, Manuela

AU - Ricklefs, Isabell

AU - Krishnamoorthy, Nandini

AU - Grossman, Nicole L.

AU - Bhakta, Nirav R.

AU - Fahy, John V.

AU - Bleecker, Eugene R.

AU - Castro, Mario

AU - Erzurum, Serpil C.

AU - Gaston, Benjamin M.

AU - Jarjour, Nizar N.

AU - Mauger, David T.

AU - Mauger, David

AU - Comhair, Suzy A.

AU - Coverstone, Andrea M.

AU - Fajt, Merritt L.

AU - Hastie, Annette T.

AU - Johansson, Mats W.

AU - Peters, Michael C.

AU - Phillips, Brenda R.

AU - Israel, Elliot

AU - Levy, Bruce D.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

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National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. Natural killer cell–mediated inflammation resolution is disabled in severe asthma. Science Immunology. 2017 Jan 1;2(9). eaam5446. https://doi.org/10.1126/sciimmunol.aam5446