L-type amino acid transporter 1 inhibitor suppresses murine Th2 cell-mediated bronchial hyperresponsiveness independently of eosinophil accumulation

Abstract

Background The activation of Th2 cells that play a pivotal role in the development of allergic eosinophilic inflammation is regulated by an L-type amino acid transporter (LAT) 1. However, the contribution of LAT1 to the pathogenesis of Th2 cell-mediated airway inflammation has not been investigated. Objective In this study, we investigated the effect of a LAT1 inhibitor, JPH203, on Th2 cell-mediated airway eosinophilic inflammation. Methods BALB/c mice were transferred with ovalbumin (OVA)-specific Th2 cell and challenged by corresponding allergen with or without administration of JPH203. Then, the infiltration of inflammatory cells including eosinophils and allergen-specific Th2 cells in the lungs and bronchial hyperresponsiveness (BHR) was assessed. Results Inflammatory responses in the lungs with massive accumulation of eosinophils and BHR were induced in Th2 cell-transferred mice upon challenge with OVA. The treatment with JPH203 significantly suppressed the allergen-induced BHR but not eosinophil infiltration. The infused Th2 cells were also accumulated in the lungs upon allergen challenge, though the response was not affected by JPH203 treatment. Conclusion JPH203 suppressed Th2 cell-mediated BHR through the mechanisms independently of the lung accumulation of eosinophils and Th2 cells.

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases

“…45 SLC7A5 inhibitor treatment suppressed allergeninduced skin inflammation in both ovalbumin (OVA)-immunized and OVA-specific Th2 cell-transferred mice and effectively suppressed allergen-induced airway and nasal hyperresponsiveness in immunized and/or Th2-transferred mice. [46][47][48][49] It is noteworthy that in CD4 + T cell differentiation models, glutamine restriction in the presence of all types of exogenous cytokine mixtures induces polarization toward Th2, whereas in the absence of Th2-induced cytokines, glutamine restriction promotes polarization toward Treg. 13 This model suggests that cytokine storm caused by viral infection may cause Th1 to tilt to Th2 phenotype when host cells ingest glutamine in large quantities.…”