Lp-PLA2-derived LysoPC drives dendritic cell immunogenic activation and Th17 inflammation in severe asthma.

Severe asthma (SA) is associated with dysregulated phospholipid metabolism, yet the underlying immunometabolic mechanisms remain poorly understood. Our metabolomic profiling of SA patients revealed a characteristic remodeling of the phosphatidylcholine (PC)-lysophosphatidylcholine (LysoPC) axis, featuring an accumulation of long-chain PC precursors and a depletion of polyunsaturated lipids. In a murine model of severe neutrophilic asthma, we identified explosive localized generation of pathogenic saturated LysoPC (particularly the 16:0 species) driven by hyperactive PC hydrolysis. Mechanistically, LysoPC acts as an endogenous danger signal that promotes the immunogenic activation of dendritic cells (DCs) by inducing a signaling "seesaw" of concurrent NF-κB activation and p38 MAPK suppression, thereby driving na ïve CD4+ T cells toward a Th17 phenotype. Crucially, the expression of lipoprotein-associated phospholipase A2 (Lp-PLA2) was robustly upregulated in both murine and human monocyte-derived DCs (moDCs) from SA patients. Importantly, pharmacological inhibition of Lp-PLA2 with darapladib reduced Th17-mediated neutrophilic inflammation in a steroid-resistant asthma model and suppressed DC immunogenicity in vitro. Collectively, our findings define the Lp-PLA2/LysoPC axis as a novel driver of DC-mediated Th17 inflammation, highlighting this pathway as a promising therapeutic target for severe asthma.