Natural isoflavone formononetin inhibits IgE-mediated mast cell activation and allergic inflammation by increasing IgE receptor degradation

• Published in: Food & function 2023-03, Vol.14 (6), p.2857-2869
• Main Authors: Zhou, Zi-Wen, Ji, Kunmei, Zhu, Xue-Yan, Wu, Xin-Ying, Lin, Ruo-Tong, Xie, Chu-Chu, Cai, Ze-Lang, Chen, Jia-Jie
• Format: Article
• Language: English
• Subjects: Allergic diseases; Anaphylaxis; Anaphylaxis - drug therapy; Animals; Cell activation; Cell Degranulation; Degradation; Gene expression; Histamine; Hypersensitivity; Immunoglobulin E; Immunoglobulin E - metabolism; Immunoprecipitation; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Isoflavones; Isoflavones - metabolism; Isoflavones - pharmacology; MAP kinase; Mast Cells; Mice; NF-κB protein; Oral administration; Ovalbumin; Passive cutaneous anaphylaxis; Proteasomes; Receptors; Receptors, IgE - genetics; Receptors, IgE - metabolism; Signal Transduction; Ubiquitin; Ubiquitination
• ISSN: 2042-6496; 2042-650X
• DOI: 10.1039/d2fo03997d

Immunoglobulin (Ig)E-associated mast cell (MC) activation triggers pro-inflammatory signals that underlie type I allergic diseases. Here, we examined the effects of the natural isoflavone formononetin (FNT) on IgE-mediated MC activation and associated mechanisms of high-affinity IgE receptor (Fc RI) signal inhibition. The effects of FNT on the mRNA expression of inflammatory factors, release of histamine and β-hexosaminidase (β-hex), and expression of signaling proteins and ubiquitin (Ub)-specific proteases (USPs) were analyzed in two sensitized/stimulated MC lines. Fc RIγ-USP interactions were detected by co-immunoprecipitation (IP). FNT dose-dependently inhibited β-hex activity, histamine release, and inflammatory cytokine expression in Fc RI-activated MCs. FNT suppressed IgE-induced NF-κB and MAPK activity in MCs. The oral administration of FNT attenuated passive cutaneous anaphylaxis (PCA) reactions and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) reactions in mice. FNT reduced the Fc RIγ chain expression, via increased proteasome-mediated degradation, and induced Fc RIγ ubiquitination by inhibiting USP5 and/or USP13. FNT and USP inhibition may be useful for suppressing IgE-mediated allergic diseases. Formononetin-inhibited IgE-mediated mast cell activation and attenuated IgE/Ag-induced allergic inflammation by suppressing USP5 or USP13 expression and increasing proteasome-mediated Fc RIγ degradation.