Intracellular Ca²⁺ balances the anti-inflammatory potential of IL-33-activated mast cells (MCs)

IL-33 is an alarmine released upon tissue injury. Mast cells (MCs) highly express the IL-33 receptor T1/ST2 (IL-33R) and are thus highly susceptible to released IL-33. Activation of the IL-33R on MCs induces the MyD88-dependent activation of the TAK1-IKK2-p65/RelA signaling pathway, ERK1/2 and p38 which together mediate the production of IL-6, IL-13 and IL-2. Whereas MC-derived IL-6 and IL-13 act as pro-inflammatory cytokines, MC-derived IL-2 acts as an anti-inflammatory cytokine by inducing T_reg cell expansion in vitro and in vivo. The mechanism, which mediate this pleiotropic nature within IL-33-activated MCs is unknown. We hypothesized that precisely balanced signaling pathways define whether MCs act as pro-inflammatory cells by the production of IL-6 and IL-13, or as anti-inflammatory cells by the production of IL-2. Surprisingly, we identified Ca²⁺ as the determinant factor, which balances the IL-33-induced production of IL-6, IL-13 and of IL-2. Thereby, whereas Ca²⁺ activates the Calcineurine (CaN)-NFATc2-ERK1/2 signaling pathway, which selectively mediates the production of IL-2, Ca²⁺ simultaneously limits the activation of p38 and the subsequent production of IL-6 and IL-13 in IL-33-activated MCs. Given that IL-2 producing MCs act as anti-inflammatory cells, our data show that the Ca²⁺-CaN-NFATc2-ERK1/2 signaling pathway determines the anti-inflammatory potential of IL-33-activated MCs.