The functionality of the cysteinyl leukotriene receptor 1 (CysLTR1) in the lung by metabolomics analysis of bronchoalveolar lavage fluid.

Abstract

Introduction: The cysteinyl leukotriene receptor 1 (CysLTR1) is known as a potent lipid mediator with a well-established role in inflammatory regulation and lung disease. While its involvement in immune cell recruitment has been previously reported, its broader impact on pulmonary metabolism remains poorly understood.

Objectives: The study aims to investigate the metabolic consequences of a CysLTR1 deletion in mice to elucidate its role in pulmonary metabolic homeostasis.

Methods: Bronchoalveolar lavage fluid (BALF) was collected from CysLTR1 knockout (KO) and wild-type (WT) mice (n = 4 per group), and analysed using standardized untargeted gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) metabolomics.

Results: Metabolomics analyses of the BALF collected from the CysLTR1 KO mice presented significantly reduced levels of glucose, glucosamine, and glyceric acid, indicating the role of the CysLTR in lung glucose uptake and consequently lung glycolysis and gluconeogenesis. This is further supported by reductions in myo-inositol and D-chiro-inositol, also supporting previous findings that this occurs due to insulin resistance. Consequential disruption of various glucose-dependent pathways, including the pentose phosphate pathway (reduced gluconic acid, sedoheptulose and xylose) and purine metabolism (reduced 1-methylinosine) indicates a consequential altered nucleotide turnover, and the significantly reduced concentrations of butanoic acid, decan-2-ol, and 1-hexadecanol, indicate changes to fatty acid metabolism in the lung, as a compensatory response to the initial glucose deficiency induced by the CysLTR1 KO. Lastly, the changes to mandelic acid, glutaric acid, tricarballylic acid, and decan-2-ol, furthermore, indicate the role of CysLTR1 in the composition/metabolism of the microbiome.

Conclusion: This study expands our knowledge on the role of CysLTR1 beyond its role in immune regulation, which may contribute to a better understanding of CysLTR1 associated lung diseases and in the development of improved therapeutic strategies.