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.

Neutrophilic Inflammation in Asthma and Association with Disease Severity

“…Using a mouse model of severe asthma that matched the Th1/Th17 profile in humans, a role for IFN-γ but not for IL-17 was observed in promoting AHR [22]. Similarly, a recently published study has identified Th1 and Th17 cells in the BAL of severe asthmatics based on chemokine receptor expression - Th1 cells being CCR6-CCR4- and Th17 cells being CCR6 + CCR4 + [27]. In this study, the frequency of Th1 but not of Th17 cells was inversely correlated with lung function (% forced expiratory volume in 1s or %FEV1) [27].…”

Tissue‐resident innate immunity in the lung

“…98 Like ILC1s, lung NK cells may contribute to chronic inflammatory disorders, such as COPD and asthma through production of inflammatory cytokines. 107 However, the importance of lung-resident NK cells, compared with recruited NKs overall, remains unclear. 105 Recently, Finch et al 106 showed increased killing of lung epithelial cells by lung NK cells, but not blood NK cells, from patients with COPD was due to DC-NK cell interactions and IL-15a transpriming.…”

“…In individuals with asthma, NKs cells in bronchoalveolar lavage fluid are skewed to a cytolytic phenotype and express higher levels of granzyme A. 107 However, the importance of lung-resident NK cells, compared with recruited NKs overall, remains unclear.…”

Interleukin-33 promotes type 1 cytokine expression via p38 MAPK in human natural killer cells

“…In addition to p38 MAPK-driven intracellular signaling leading to transcription factor activation, p38 MAPK can also directly phosphorylate membrane proteins like ADAM17 32 . The activation of ADAM17 by p38 MAPK can promote shedding of TNF 17,33 . Our data are consistent with these possibilities, revealing p38 MAPK-dependent enhancement of TNF expression coupled to ADAM17-dependent release of cell-associated TNF.…”

“…In macrophages, IL-33 stimulates activation of p38 MAPK 17,18 . To determine if IL-33 activates p38 MAPK in human NK cells, we measured phosphorylation of p38 MAPK and downstream targets of this kinase by flow cytometry.…”