ABSTRACT Dysregulated chronic inflammation underlies a spectrum of severe asthma phenotypes, among which neutrophilic asthma (NA) represents a treatment‐recalcitrant endotype characterized by Th17‐driven airway inflammation and steroid resistance. Although lipid mediators are known to play dual roles in promoting and resolving inflammation, the lipid species governing the Th17‐neutrophil axis in NA remain unknown. Here, through integrated lipidomic profiling of clinical samples (exhaled breath condensate, plasma, sputum) from an NA cohort and a murine model of Th17‐driven airway inflammation, a deficiency in very‐long‐chain ceramides, notably Cer24:1, was identified. This reduction correlated with disease severity and neutrophilic inflammation. In vivo, Cer24:1 supplementation alleviated airway hyperresponsiveness and neutrophilic infiltration, while Smpd1 knockout mice—with impaired ceramide generation—displayed exacerbated Th17 pathology. Using structure‐guided molecular docking, surface plasmon resonance, and functional assays, Cer24:1 was shown to directly target the prostaglandin E2 receptor EP2 on CD4 + T cells. This interaction suppressed JAK2–STAT3 signaling and RORγt‐driven Th17 differentiation. Notably, PGE 2 competitively reversed Cer24:1's protective effects, further supporting EP2‐dependent modulation. Our results reveal Cer24:1 as an endogenous pro‐resolving lipid that constrains neutrophilic inflammation via direct modulation of the EP2–STAT3 axis in Th17 cells, providing a new metabolic checkpoint and potential therapeutic strategy for severe neutrophilic asthma.
Liu et al. (Fri,) studied this question.