MRGPRX2 mediates immediate-type pseudo-allergic reactions induced by iodine-containing iohexol

[Display omitted] •Iohexol induces pseudo-allergic reactions in mice via mast cells.•MRGPRX2 mediates iohexol-induced LAD2 cells activation.•Iodine might be a key player in iohexol-induced pseudo-allergic reactions.•Regulate dosage regimen might be useful to reduce iohexol-induced allergic reactions. Iohexol is a typical iodinated radiocontrast medium and widely used in clinical angiography. Hypersensitivity reactions induced by iohexol are common side effects known to increase the risk for patients. Iodine is the main functional group of iohexol, and it can induce delayed anaphylaxis. However, iohexol also induces immediate-type allergies, but the underlying mechanism is still not clear. MRGPRX2 is a key receptor present on mast cells, which mediates pseudo-allergic reactions induced by various drugs. We aimed to verify the relationship between iohexol-induced anaphylactic reactions and MRGPRX2. MRGPRX2-mediated pseudo-allergic reactions induced by iohexol were investigated in vivo and in vitro using a mouse model of local and systemic anaphylaxis and mast cell degranulation assays, respectively. Iohexol caused pseudo-allergic reactions in wild-type (WT) mice by activating mast cells to release histamine and cytokines. However, it did not induce a similar phenomenon in KitW-sh/W-sh (MUT) mice. Iohexol stimulated intracellular calcium ion (Ca2+) influx in MRGPRX2-HEK293, MrgprB2-HEK293, and LAD2 cells but not in NC-HEK293 cells. After knockdown of MRGPRX2 expression in LAD2 cells, the degree of iohexol-induced degranulation was reduced. In addition, after structural modification of iohexol by removal of iodine, a reduction in iohexol-induced effects, such as local and systemic anaphylaxis in mice and degranulation of LAD2 cells, could be observed. Iohexol was shown to induce immediate-type pseudo-allergic reactions via MRGPRX2, which was dependent on the presence of iodine. Conclusively, inhibition of MRGPRX2-mediated mast cell degranulation and cytokine release is important to prevent iohexol-induced immediate-type pseudo-allergic reactions.