Constitutively high levels of endogenous soluble ST2 inhibit food allergic responses in mice
Abstract
IL-33-induced signals via membrane-bound ST2 (ST2L) are critical for allergies. However, the physiological role of endogenous soluble ST2 (sST2) remains elusive. Here, we generated sST2-deficient mice with intact ST2L using the CRISPR/Cas9 system. Skin fibroblasts constitutively released sST2 protein at extremely high levels compared to mast cells, which did not reflect the expression levels of sST2 mRNA. This discrepancy can be partly explained by the sST2 protein degradation mediated by mast cell proteases. Accordingly, sST2 deficiency did not affect IL-33- and/or IgE plus antigen-stimulated mast cell activation in vitro. We provided evidence that constitutively high levels of sST2 suppress food allergies in mice by inhibiting IL-33-dependent, both expansion of jejunum mast cells and enhancement of their degranulation. Analysis of bone marrow chimeric mice under steady-state conditions showed that circulating sST2 was derived almost equally from hematopoietic and nonhematopoietic cells. Increased circulating sST2 in food-allergic mice was possibly and partly derived from fibroblasts stimulated by locally released IL-4 and IL-13. In conclusion, endogenous sST2 contributes to the suppression of food allergies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Mayuki Kojima
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Kumi Izawa
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Tomoaki Ando
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Keiko Maeda
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Ayako Kaitani
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Nobuhiro Nakano
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Risa Yamamoto
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Shunichi Miyazaki
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Mayu Shinagawa
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Mio Sasaki
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Anna Kamei
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Akie Maehara
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Naoko Negishi
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Hiromichi Yamada
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Shino Uchida
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Eisuke Inage
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine
Yoshikazu Ohtsuka
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine
Susumu Nakae
Graduate School of Integrated Sciences for Life, Hiroshima University
Hideoki Ogawa
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Ko Okumura
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Hiromichi Shoji
Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine
Toshiaki Shimizu
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine
Jiro Kitaura
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine