Role of the IRE1α-XBP1 Axis in IgE-Dependent Activation of Mast Cells

The IRE1α-XBP1 axis is the most conserved of the three major unfolded protein response (UPR) branches triggered by the endoplasmic reticulum (ER) stress. Although the transcription factor XBP1 is involved in the development and function of several hematopoietic lineages, its role in the activation of mast cells (MCs), which are critical in allergic responses, remains largely unknown. We identified salicylaldehyde, which suppresses IRE1α nuclease activity that is essential for XBP1 production, as an inhibitor of MC activation in our previous screening; therefore, we herein investigated the effects of additional IRE1α inhibitors, 3-methyl-6-bromo-salichylaldehyde (MBSA) and KIRA6, targeting the nuclease domain and kinase domain, respectively, on MC activation. MBSA and KIRA6 suppressed IgE-dependent degranulation of bone marrow-derived MCs (BMMCs) but did not inhibit Ca²⁺ ionophore- or compound48/80-induced degranulation. Treatments with inhibitors of two other branches of UPR, the PERK and ATF6 pathways, did not affect the IgE-induced activation of BMMCs. The intraperitoneal administration of MBSA or KIRA6 significantly suppressed IgE-induced passive anaphylaxis in mice. Furthermore, to examine the effects of XBP1, siRNA-mediated knockdown was performed. The results obtained confirmed that Xbp1 siRNA introduction reduced the IgE-dependent degranulation of BMMCs in parallel with the knockdown level of Xbp1 mRNA. Therefore, the IRE1α-XBP1 axis plays a significant role in IgE-dependent and MC-mediated allergic responses and is considered to be a therapeutic target of allergic diseases.