A joint research group from Juntendo University and Hiroshima University has revealed that "soluble ST2 (sST2)" present in the body suppresses food allergies.
When epithelial cells are damaged by the invasion of food antigens, cytokines such as IL-33 are released. Among the IL-33 receptors, the membrane-bound ST2 (ST2L) present on the cell surface captures IL-33 and transmits a signal, inducing the production of type 2 cytokines such as IL-4 and IL-13, causing "type 2 inflammation," which is considered central to the pathogenesis of food allergies. On the other hand, the role of endogenous sST2, an IL-33 receptor that is maintained at high concentrations in the body, has not been fully elucidated until now.
In this study, to elucidate the role of sST2, we created a novel genetically modified mouse in which ST2L is normally expressed but only sST2 is deficient. Using this mouse, we analyzed the effects of IL-33 addition and found that sST2 deficiency did not directly affect the degranulation of small intestinal mast cells that cause allergic symptoms, nor did it directly affect IL-9-producing mucosal mast cells induced by IL-33. However, it was revealed that cytokine production when fibroblasts were stimulated with IL-33 increased with sST2 deficiency. Fibroblasts constitutively produce more than 10 times the amount of sST2 as mast cells, and it was thought that this large amount of sST2 suppresses IL-33 signaling in a steady state.
Furthermore, when food allergies were induced and analyzed in sST2-deficient mice, food allergies worsened compared to normal mice, and the number of mast cells and degranulation rate in the small intestine, as well as the expression levels of type 2 cytokines and IL-33, were all increased. Since molecules contained in granules (such as histamine) cause food allergy symptoms, the more mast cells and the higher the degranulation rate, the worse the food allergy. On the other hand, when sST2-deficient mice were administered ST2-Fc, which mimics sST2, the number of mast cells and degranulation rate decreased, and food allergy symptoms were suppressed.
These results suggest that sST2 inhibits IL-33 signaling, thereby suppressing the increase of small intestinal mast cells and enhanced degranulation, and preventing the exacerbation of food allergies. This study represents a significant achievement that could lead to the development of new preventive and therapeutic methods for food allergies targeting sST2 and IL-33 signaling.
