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Multifaceted functions of SiglecF expressing neutrohpils in the exacerbation of air pollutant-induced airway inflammation

ABSTRACT: Diesel exhaust particles (DEPs) are the main component of traffic-related air pollution and implicated in asthma pathogenesis and exacerbation. However, the mechanistic link between DEP exposure and worsening asthma symptoms remains unclear. Here, we characterized a unique subset of neutrophils that express a high level of Sialic acid-binding, Ig-like lectin (Siglec)-F. DEP exposure instructs SiglecF expression on neutrophils by increasing P2X1 receptors sensing damage-associated molecular patterns (DAMPs) molecules, ATP. SiglecFhigh neutrophils stimulated by DEP release neutrophil extracellular traps (NETs) to cause tissue damage and IL-17A production, and potentiated type 2 cytokine production by producing cysteinyl leukotrienes. As a result, SiglecFhigh neutrophils worsen airway hyperresponsiveness (AHR) as well as airway inflammations. We also confirmed that siglec8, corresponding to murine SiglecF, expression increased in neutrophils from patients with asthma, and they correlated with the severity of the disease. Together, these translational findings suggest a novel SiglecF expressing neutrophils in the development of severe asthma by linking type 2 and type 3 responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE158040 | GEO | 2022/09/01

REPOSITORIES: GEO

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Project description:Background: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published. Methods: We conducted a genome-wide analysis of microRNA and messenger RNA (mRNA) in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis (WGCNA) was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes, and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway. Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for toll-like receptor (TLR) and Th17 signaling, and endoplasmic reticulum stress. Hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma. Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.

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Multifaceted functions of SiglecF expressing neutrohpils in the exacerbation of air pollutant-induced airway inflammation

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