What Are Those Neutrophils Doing in Severe Asthma Anyway?

BACKGROUND: Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood. OBJECTIVE: We hypothesized that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses. METHODS: Sixty seven children with severe asthma refractory to high-dose inhaled corticosteroid (ICS) treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil “high” versus “low” groups based on BAL differential counts. Neutrophil activation markers, functional assays and phenotyping studies were performed as well as airway macrophage functional assays. Results were compared to those from children with moderate asthma treated with ICS. RESULTS: Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway pro-inflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-β1 the neutrophils were not more apoptotic. Instead, neutrophils had a highly pro-inflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more pro-inflammatory with impaired phagocytosis and increased apoptosis. CONCLUSIONS: Children with neutrophil-predominant severe asthma have pro-inflammatory neutrophils with enhanced survival. Airway macrophages are also pro-inflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.