Locally instructed CXCR4(hi) neutrophils trigger environment-driven allergic asthma through the release of neutrophil extracellular traps

Low exposure to microbial products, respiratory viral infections and air pollution is a major risk factor for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing (scRNA-seq), we characterized lung neutrophils in mice exposed to a pro-allergic, low dose of lipopolysaccharides (LPS(lo)) or a protective, high dose of LPS (LPS(hi)) before exposure to house dust mite (HDM). Unlike exposure to LPS(hi), exposure to LPS(lo) instructed recruited neutrophils to upregulate the expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps (NETs). The LPS(lo)-induced neutrophils and NETs potentiated the uptake of HDM by CD11b(+)Ly-6C(+) dendritic cells (DCs) and type 2 allergic airway inflammation in response to HDM. NETs derived from CXCR4(hi) neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma.