Nociceptor neurons control pollution-mediated neutrophilic asthma.

The immune and sensory nervous systems, having evolved in parallel, communicate through shared receptors and transmitters to maintain homeostasis and respond to both external and internal disruptions. Although neural responses often confer protective benefits, they can also exacerbate inflammation during allergic reactions such as asthma. In our study, we modeled pollution-exacerbated asthma by exposing mice to ambient PM2.5 particles alongside ovalbumin. Compared to exposure to ovalbumin alone, this co-exposure significantly increased the numbers of neutrophils and γδ T cells in bronchoalveolar lavage fluid and lung tissue, respectively. We found that silencing nociceptor neurons at the peak of inflammation using intranasal QX-314 or ablating Trpv1-expressing neurons reduced lung neutrophil accumulation. Live in vivo intravital imaging confirmed that neuronal ablation reduced neutrophil numbers and increased their net displacement capacity. In neurons isolated from mice with pollution-exacerbated asthma, the chemical-sensing TRPA1 channel exhibited heightened sensitivity to its cognate ligand. Elevated levels of artemin were detected in the bronchoalveolar lavage fluid of pollution-exposed mice but returned to baseline in mice with ablated nociceptor neurons. Alveolar macrophages expressing the pollution-sensing aryl hydrocarbon receptor were identified as a putative source of artemin following exposure to PM2.5. This molecule enhanced TRPA1 responsiveness and, in turn, drove nociceptor-mediated neutrophil recruitment, revealing a novel mechanism by which lung-innervating neurons respond to air pollution in the context of allergy. Overall, our findings suggest that targeting artemin-driven pathways could provide a therapeutic strategy for controlling neutrophilic airway inflammation in asthma, a clinical condition typically refractory to treatment.