IL-33-activated murine mast cells control the dichotomy between RORγt+ and Helios+ Tregs via the MK2/3-mediated IL-6 production in vitro

Abstract

In mast cells, IL-33 typically induces the activation of NF-κB, which results in the production of cytokines such as IL-6 and IL-2. Here, we demonstrate that the IL-33-induced IL-6 production in murine mast cells and the formation of RORγt⁺ T_regs essentially depends on the MAPKAPs, MK2, and MK3 (MK2/3) downstream of MyD88. In contrast to this, the IL-33-induced and MyD88-dependent IL-2 production in mast cells contributes to the maintenance of Helios⁺ T_regs . Thereby, the IL-33-induced IL-2 response and, thus, the maintenance of Helios⁺ T_regs are limited by an IL-6-mediated autocrine negative feedback stimulation acting on mast cells. Collectively, we present MK2/3 in IL-33-activated mast cells as a signaling node, which controls the dichotomy between RORγt⁺ T_reg and Helios⁺ T_reg in vitro.

Keywords: IL-33; IL-6; MK2/3; Mast cells; Tregs.