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

Background: Obese asthma is increasingly recognized as a distinct clinical phenotype marked by greater severity and a non-type 2 inflammatory profile. Obesity-associated lipid dysregulation may contribute to its pathogenesis through immunomodulatory mechanisms. This study aimed to characterize the glycerophospholipid profile in obese asthma and to investigate its functional role in modulating immune responses.Methods: We performed targeted lipidomic analysis of serum glycerophospholipids from obese and non-obese patients with asthma. A house dust mite (HDM) induced asthma model was established in diet-induced obese (DIO) mice to evaluate pulmonary pathology and immune polarization. The immunomodulatory effects of lysophosphatidylcholine (LPC) 18:2 were assessed using both in vivo experiments and in vitro T helper 17 (Th17) differentiation assays. Cellular uptake of LPC by na ve CD4 T cells was quantified to explore the mechanism underlying its reduced systemic abundance.Results: Lipidomic profiling revealed a distinct glycerophospholipid signature in obese asthma, with LPC 18:2 exhibiting the most pronounced reduction. Obese asthmatic mice exhibited exacerbated airway inflammation with a dominant Th17-type immune response. 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. Mechanistically, na ve 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.Conclusions: Our findings highlight LPC 18:2 as a potential metabolic regulator linking obesity-associated metabolic disturbances to pathological Th17-skewed immune responses. Modulation of LPC signaling may therefore represent a novel therapeutic strategy for this refractory asthma endotype.