Network toxicology identifies IL-6/IL-1β-linked Th17/ILC3 responses in DEHP-induced neutrophilic asthma

Environmental plasticizers are increasingly implicated in asthma susceptibility, yet the mechanisms linking chemical exposure to airway inflammation remain poorly defined. Here we show that the plasticizer di(2-ethylhexyl) phthalate (DEHP) directly drives a neutrophil-dominant asthma phenotype through activation of IL-17-centered immune pathways. Integrative network toxicology identified IL-6 and IL-1β as central inflammatory nodes connecting DEHP exposure with Th17 differentiation and IL-17 signaling. Consistent with these predictions, inhalational DEHP exposure in mice induced airway hyperresponsiveness, mixed granulocytic airway inflammation, mucus hypersecretion, and elevated pulmonary IL-6, IL-1β, and IL-17A expression. Immune profiling revealed expansion of IL-17A-producing lymphocytes, including Th17 cells and type 3 innate lymphoid cells (ILC3s). Genetic ablation of IL-17A markedly attenuated airway hyperresponsiveness and neutrophilic inflammation following DEHP exposure. Together, these findings identify an IL-6/IL-1β-Linked Th17/ILC3 axis as a mechanistic link between environmental plasticizer exposure and non-type 2 asthma, providing a conceptual framework for pollutant-driven airway disease.