Lysophosphatidylcholine 18:2 exacerbates Th17-dominant inflammation in obese asthma

TL;DR

This study shows that a specific lipid, LPC 18:2, worsens inflammation in obese asthma by promoting harmful immune responses.

Contribution

The study identifies LPC 18:2 as a novel lipid mediator linking obesity to Th17-driven asthma inflammation.

Findings

LPC 18:2 levels are reduced in obese asthma patients and mice.

Exogenous LPC 18:2 worsens airway inflammation and Th17 polarization in obese mice.

LPC 18:2 directly promotes Th17 differentiation in a dose-dependent manner.

Abstract

Obese asthma is increasingly recognized as a distinct clinical phenotype, often associated with greater disease severity and non–type 2–skewed inflammation. Obesity-associated lipid dysregulation may contribute to its pathogenesis through immunomodulatory mechanisms. This study aimed to characterize the glycerophospholipid profile of obese asthma and to investigate the functional impact of candidate lipids on immune responses.

We performed targeted lipidomic analysis of serum glycerophospholipids in patients with overweight/obese asthma and those with normal-weight asthma. A house dust mite (HDM)–induced asthma model was established in diet-induced obese (DIO) mice to evaluate pulmonary pathology and T-cell immune polarization. The immunomodulatory effects of lysophosphatidylcholine (LPC) 18:2 were assessed using in vivo experiments and in vitro T helper 17 (Th17) differentiation assays. Cellular uptake of LPC by naïve CD4⁺ T cells was quantified to explore the mechanism underlying the reduced circulating abundance of LPC 18:2.

Lipidomic profiling revealed a differential glycerophospholipid signature in obese asthma, with LPC 18:2 exhibiting the most pronounced reduction. Obese asthmatic mice exhibited exacerbated airway inflammation consistent with a Th17-skewed immune response. Despite reduced circulating levels, administration of exogenous LPC 18:2 further aggravated airway inflammation and selectively enhanced Th17 polarization in these mice. In vitro assays confirmed that LPC 18:2 directly promotes Th17 differentiation in a dose-dependent manner. Mechanistically, naïve CD4⁺ T cells from obese mice showed increased LPC uptake, potentially explaining both the reduced circulating LPC 18:2 levels and its amplified pro-inflammatory effects in obese asthma.

Our findings highlight LPC 18:2 as a potential metabolic regulator that may link obesity-associated lipid disturbances to pathological Th17-skewed immune responses. Modulation of LPC 18:2–related pathways may therefore represent a novel therapeutic strategy for this asthma phenotype.

The online version contains supplementary material available at 10.1186/s12944-026-02907-4.

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