Tetrahydrocurcumin suppresses FcεRI- and MRGPRX2-mediated mast cell activation and attenuates peanut-induced anaphylaxis in an in vitro and in vivo study.

BACKGROUND: Tetrahydrocurcumin (THC), a major reductive metabolite of curcumin, possesses improved chemical stability and anti-inflammatory properties. However, its direct effects on mast cell-mediated allergic responses remain poorly defined. We investigated whether THC suppresses FcεRI-dependent and selected IgE-independent mast cell activation and protects against peanut-induced anaphylaxis in vivo. METHODS: Primary murine bone marrow-derived mast cells and human LAD2 mast cells were stimulated through IgE/FcεRI crosslinking or MRGPRX2-related activation. Mast cell degranulation, cytokine production (CCL2, TNF, IL-6, and IL-13), and cytotoxicity were evaluated. The in vivo efficacy of orally administered THC was assessed in a mouse model of peanut-induced anaphylaxis. RESULTS: THC dose-dependently inhibited IgE/FcεRI-mediated mast cell degranulation and suppressed inflammatory cytokine production without detectable cytotoxicity. Under the tested conditions, THC exhibited greater inhibitory activity than pemirolast potassium. THC also suppressed ionomycin- and MRGPRX2-mediated mast cell activation and remained effective when administered before or at the initiation of activation. In peanut-sensitized mice, repeated oral THC administration significantly reduced anaphylactic hypothermia and intestinal inflammatory responses. CONCLUSION: THC suppresses FcεRI-dependent and MRGPRX2-dependent pathways and attenuates peanut-induced anaphylactic responses in vivo. These findings support the potential of THC as a mast cell-modulating compound for allergic and anaphylactic disorders.