AUTHOR=Matsushima Goshi , Matsui Yuri , Okamoto Hanano , Umeda Nagisa , Kakimoto Mai , Mino Megumi , Nakagawa Tadashi , Ishii Kaori , Matsuo Yoshimi , Matsubara Daiki , Tanaka Akio , Ogata Koji , Yoshii Michiko , Goda Mitsuhiro , Yanase Yuhki , Hosoi Toru , Ozawa Koichiro 

TITLE=Unique compound with anti-allergic action: inhibition of Lyn kinase activity by KIRA6

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1625798

DOI=10.3389/fphar.2025.1625798

ISSN=1663-9812

ABSTRACT=Mast cells and basophils play important roles in allergic disorders associated with specific antigens and IgE. Crosslinking of the high-affinity IgE receptor (FcεRI) by specific antigens activates several tyrosine kinases, such as Lyn and spleen-associated tyrosine kinase (Syk), resulting in the release of calcium ions (Ca2+) from the endoplasmic reticulum (ER) into the cytoplasm. As Ca2+ release from the ER is essential for the release of pro-inflammatory mediators, ER stress-related molecules, such as inositol-requiring enzyme 1α (IRE1α), may play roles in mast cell and basophil activation. However, the associations between ER stress-related molecules and mast cell and basophil activation remain unclear. In this study, we aimed to investigate the roles of ER stress-related molecules in mast cell and basophil activation. Activation of the IRE1α-spliced form of the X-box binding protein 1 (sXBP1) axis, an ER stress-related pathway, was observed during the antigen-induced activation of mast cells. Moreover, the IRE1α inhibitor, KIRA6, suppressed antigen-induced release of pro-inflammatory mediators from rat basophilic leukemia (RBL)-2H3 cells, bone marrow-derived mast cells (BMMCs), human basophils, and human mast cells at low doses (<1 μM). However, to our surprise, IRE1α knockout did not inhibit antigen-induced release of pro-inflammatory mediators. Instead, KIRA6 blocked the antigen-induced activation of Syk by inhibiting kinase activity of Lyn. Additionally, KIRA6 exerted anti-allergic effects in vivo. Overall, our findings suggest that KIRA6 prevents allergic reactions by inhibiting the kinase activity of Lyn via an IRE1α-independent pathway.