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<p>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<sup>+</sup> 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Fang Wang,
  • Zhihui Min,
  • Yuhao Qian,
  • Jiameng Gao,
  • Zhenlin Yang,
  • Zhilong Jiang,
  • Zhihong Chen

摘要

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.

Graphical Abstract