Contribution of monocyte and macrophage extracellular traps to neutrophilic airway inflammation in severe asthma

Background: Increased blood/sputum neutrophil counts are related to poor clinical outcomes of severe asthma (SA), where we hypothesized that classical monocytes (CMs)/CM-derived macrophages (M9) are involved. We aimed to elucidate the mechanisms of how CMs/M9 induce the activation of neutrophils/ innate lymphoid cells (ILCs) in SA. Methods: Serum levels of monocyte chemoattractant protein-1 (MCP-1) and soluble suppression of tumorigenicity 2 (sST2) were measured from 39 patients with SA and 98 those with nonsevere asthma (NSA). CMs/M9 were isolated from patients with SA (n = 19) and those with NSA (n = 18) and treated with LPS/interferon-gamma. Monocyte/M1M9 extracellular traps (MoETs/M1ETs) were evaluated by western blotting, immunofluorescence, and PicoGreen assay. The effects of MoETs/M1ETs on neutrophils, airway epithelial cells (AECs), ILC1, and ILC3 were assessed in vitro and in vivo. Results: The SA group had significantly higher CM counts with increased migration as well as higher levels of serum MCP-1/sST2 than the NSA group. Moreover, the SA group had significantly greater production of MoETs/M1ETs (from CMs/M1M9) than the NSA group. The levels of MoETs/M1ETs were positively correlated with blood neutrophils and serum levels of MCP-1/sST2, but negatively correlated with FEV1%. In vitro/in vivo studies demonstrated that MoETs/M1ETs could activate AECs, neutrophils, ILC1, and ILC3 by increased migration as well as proinflammatory cytokine production. Conclusions: CM/M9-derived MoETs/M1ETs could contribute to asthma severity by enhancing neutro-philic airway inflammation in SA, where modulating CMs/M9 may be a potential therapeutic option. (c) 2023 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).