Role of the IRE1α-XBP1 axis in IgE-dependent activation of mast cells

Abstract The IRE1α-XBP1 axis is the most conserved of three major unfolded protein response (UPR) branches that are triggered by the endoplasmic reticulum (ER) stress. Although the transcription factor XBP1 is involved in the development and function of several hematopoietic lineages, the role of XBP1 in the activation of mast cells (MCs) that play key role in allergic response remains largely unknown. Because we have identified salicylaldehyde (SA), which inhibits IRE1α nuclease activity that is essential for production of XBP1, as an inhibitor of MC activation in our previous screening, we investigated the effects of additional IRE1α inhibitors, 3-methyl-6-bromo-salichylaldehyde (MBSA) and KIRA6, targeting nuclease domain and kinase domain, respectively, on MC activation. MBSA and KIRA6 suppressed IgE-dependent degranulation and cytokine release of bone marrow-derived MCs (BMMCs), whereas these inhibitors did not suppress the Ca 2+ ionophore- or compound48/80-induced degranulation. Treatment with inhibitors against two other branches of UPR, the PERK and the ATF6 pathways, did not affect IgE-induced activation of BMMCs. Intraperitoneal administration of MBSA or KIRA6 significantly suppressed IgE-induced passive anaphylaxis in mice. Furthermore, to evaluate the effect of XBP1, siRNA-mediated knockdown was performed. It was confirmed that Xbp1 siRNA introduction reduced IgE-dependent degranulation of BMMCs in parallel with the knockdown level of Xbp1 mRNA. Taken together, the IRE1α-XBP1 axis plays a significant role in IgE-dependent and MC-mediated allergic response, which is considered to be therapeutic target of allergic diseases.