Endogenous IL-33 determines the severity of Th17 cell-mediated inflammation by regulating the phenotype of antigen-presenting cells

J Immunol. 2026 Nov 2;215(11):vkag285. doi: 10.1093/jimmun/vkag285.

ABSTRACT

Cytokines of the interleukin (IL)-1 family are key mediators of cutaneous innate immunity. While the activation and function of IL-1β and IL-18 during immune responses are well characterized, the immunological properties of IL-33 are less well understood. The functions of exogenous IL-33, the therapeutic application of recombinant IL-33, and the interaction between IL-33 and its receptor ST2 are largely elucidated. In contrast, the function of endogenous IL-33 (eIL-33) is yet unknown. By investigating the immune responses in 2 different Th17-mediated experimental disease models, autoimmune encephalomyelitis and imiquimod-induced psoriasis, we found that eIL-33 dampened the Th17 immune response in vivo. Mechanistically, the absence of eIL-33 induced a stronger proinflammatory phenotype in dendritic cells (DCs), resulting in a stronger Th17 response in vivo and in vitro. Furthermore, eIL-33 influenced the expression of costimulatory molecules on antigen-presenting cells. On the molecular level, eIL-33 regulated genes like Icosl, Il12b, and Ccl17, which are associated with inflammatory autoimmune diseases. These findings demonstrate that the pleiotropic cytokine IL-33 influences, depending on its exogenous secreted or endogenous intracellular form, several signaling pathways. With these data we could unravel the mechanism of how intracellular IL-33 influences the phenotype of DCs to attenuate the differentiation of pathogenic Th17 cells.

PMID:43024832 | DOI:10.1093/jimmun/vkag285