Itaconate Modulates Neutrophil Homeostasis to Ameliorate Airway Inflammation in Diesel Exhaust Particles-exacerbated Asthma via Inhibiting NETs Formation

TL;DR

Itaconate reduces airway inflammation in asthma worsened by diesel exhaust by blocking harmful immune cell activity.

Contribution

Itaconate is shown to inhibit neutrophil extracellular traps and Th17 cell activation in corticosteroid-resistant asthma.

Findings

Neutrophils regulate DEP-induced asthma via NF-κB signaling and ACOD1/itaconate.

Itaconate treatment reduces inflammation and corticosteroid resistance in asthma models.

Itaconate suppresses NETs and Th17 differentiation, balancing immune responses.

Abstract

Particulate matter exposure, especially diesel exhaust particles (DEP), can exacerbate neutrophilic airway inflammation which presents corticosteroid insensitivity, resulting in the loss of asthma control. The underlying biological mechanisms remain poorly understood, thereby impeding the development of innovative therapeutic strategies. Itaconate (ITA) is an anti-inflammatory metabolite that suppresses excessive immune activation in multiple pathological conditions. In this study, we identified that neutrophil acted as an essential regulator in DEP-induced corticosteroid-resistant asthma mouse models. Multi-omics and single-cell sequencing analysis found that aconitate decarboxylase 1 (ACOD1)/ITA was significantly elevated in neutrophils via the NF-κB signaling pathway in DEP-exacerbated asthma. Knockout of Acod1 exacerbated asthma pathogenesis, while treatment with exogenous ITA or 4-octyl itaconate (4-OI) conferred protection against airway inflammation and reversed corticosteroid resistance in asthma mouse models. Mechanistically, neutrophil-derived ITA helped maintain immune homeostasis by reducing the formation of neutrophil extracellular traps (NETs), which further inhibited Th17 cell differentiation in DEP-exacerbated asthma. Our results delineate the dual immunoregulatory function of neutrophils in DEP-induced corticosteroid-resistant asthma, wherein they simultaneously propagate inflammation through NETosis and Th17 activation while restraining immune hyperactivation via ITA-mediated metabolic regulation. ITA serves as a negative regulator of airway inflammation and corticosteroid resistance, highlighting its promising therapeutic potential in asthma.

Figures