Dividing neutrophils in subsets reveals a significant role for activated neutrophils in the development of airway hyperreactivity

Abstract

Background: Previous research has emphasized the importance of eosinophils in allergic asthma, while paying less attention to neutrophils. The known functionality of neutrophils in the inflammatory process has recently changed and knowledge about subsets of neutrophils, as characterized by their expression of CD16 and CD62L, has surfaced. Their specific roles in asthma are still unknown.Objective: To study the functional differences between subsets of neutrophils by characterizing the impact of individual subsets on airway smooth muscle reactivity. Methods:The direct effect of neutrophils on airway hyperresponsiveness was assessed by co-culturing different subsets of neutrophils (produced by LPS in vitro stimulation) with human isolated small airways or murine tracheae with subsequent evaluation of smooth muscle reactivity to bradykinin in myographs. Supernatants and tissue were saved for ELISA and immunohistochemistry.Results: The CD16 high CD62L dim neutrophils were found to enhance the response to bradykinin in both human isolated small airways and murine tracheae. No such effects were obtained for the other subsets. The response is due to an upregulation of bradykinin receptor 2 through release of TNFα from the neutrophil.Conclusions and Clinical Relevance: The present study introduces a new concept regarding the role of neutrophils and defines a novel direct link between a specific activated neutrophil subset and airway smooth muscle, establishing neutrophils as important players in the development of asthmatic airway hyperactivity.

Subsetting reveals CD16high CD62Ldim neutrophils in chronic rhinosinusitis with nasal polyps

“…The expressed levels of CD11b were markedly increased on CD16 high CD62L high and CD16 high CD62L dim neutrophils in patient blood, nasal mucosa, and polyps The same subset has been shown to enhance bradykinin-dependent contraction of smooth muscle cells in airways, suggesting a role for neutrophils in asthmatic airway hyperactivity. 3 More than 10% of the Western population suffers from CRS, and recent findings have stressed the immunological complexity of the disease, making it obvious that the concept of Th1/Th2 inflammation is not sufficient to explain the pathology. S aureus is found intramucosally, and colonizing the mucosal surface and its products has been demonstrated within the polyp tissue-stimulating immune responses.…”

“…1,2 House dust mites serve as carriers of bacteria, and it is possible that these bacteria are responsible for the induction of IgE sensitization to microbial antigens. 3 For this reason, the microbiomes of allergen-producing mites have recently become the subject of intensive research. 4 Unfortunately, the existence of variability in microbiome composition among different mite populations or strains is insufficiently considered (Erban et al, 5 Lee et al 6 ), despite the evidence that different strains of mites may harbor different and persistent microbial communities.…”

“…The CD16 high CD62L dim subset, regarded activated, exhibited T cell–suppressing capacities and decreased adherence to the endothelium during induced acute inflammatory conditions . The same subset has been shown to enhance bradykinin‐dependent contraction of smooth muscle cells in airways, suggesting a role for neutrophils in asthmatic airway hyperactivity …”

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

“…However, this effect was not observed in other subsets of neutrophils. Upregulation of bradykinin receptor 2 via tumor necrosis factor‐α release from the neutrophil represent a direct crosstalk between airway smooth muscle and activated neutrophil subset thus highlighting neutrophils as a key regulator of asthmatic airway hyperactivity (Ekstedt, Säfholm, et al, ).…”

“…Neutrophil subsets are categorized by low or high expression of CD16 and CD62L (Ekstedt et al, ; Ekstedt, Säfholm, Georén, & Cardell, ). The CD16 high CD62L dim neutrophils can enhance the response of human isolated small airways and murine trachea to bradykinin.…”