Jun Nagai, PhD
Allergy and Clinical Immunology
Jun Nagai*, Sofia A. Marshall, Kendall Zaleski, Joshua A. Boyce
Joshua A. Boyce
The cysteinyl leukotrienes (cysLTs) are lipid mediators that play validated roles in asthma and are generated from arachidonic acid by activated mast cells (MCs), eosinophils, macrophages. Type 1 cysteinyl leukotriene receptor (CysLT1R) antagonists provide clinical benefit for patients with asthma and allergic rhinitis. The type 2 cysteinyl leukotriene receptor (CysLT2R) possesses poorly understood cell type- or stimulus-dependent functions that may either protect from or promote Type 2 immunity in allergic inflammation. We previously demonstrated that LTC4 potently activates mouse platelets through CysLT2R, and drives allergen-induced type 2 pulmonary inflammation when protective PGE2 signal is low. Paradoxically, however, CysLT2R signaling suppresses allergen-induced pulmonary inflammation in wild-type mice. In this study, we identified the CysLT2R signaling responsible for the protective effect in mast cells. CysLT2R signaling blocked CysLT1R-induced p44/42 (ERK1/2) MAP kinase phosphorylation in human mast cells. The PKA inhibitor H89 blocked CysLT2R-induced desensitization of CysLT1R-dependent MAP kinase activation in mast cells. CysLT2R-dependent desensitization of CysLT1R-dependent MAP kinase activation in mast cells through PKA activation may play a protective role in allergic inflammation. We recently demonstrated that the protective CysLT2R/PKA axis can be distinguished from proinflammatory CysLT2R signaling by platelets. We will talk about the potential of CysLT2R biased agonists that lack (and antagonize) proinflammatory properties but retain the ability to convey protective CysLT2R/PKA signaling as potential treatments for asthma.
The current therapeutic strategy for asthma, which is based mainly on inhaled corticosteroids, CysLT1R antagonists and β2 agonists, relies on symptomatic control rather than addressing the pathogenesis of a disease and is still not sufficient to control symptoms. Particularly, interpatient variability in response to CysLT1R antagonists is significant, with 24% to 78% of patients receiving CysLT1R antagonists being classified as non-responders. The development of CYsLT2R biased agonist may overcome the current clinical issues of unresponsiveness to CysLT1R antagonists and the lack of disease modifying effects of existing drugs.