Cellular mechanisms of IL-33 and their relation to MDD risk. (1) Early life stress precipitates increased expression of neuroimmune genes, potentially via norephinephrine and epinephrine release, (2) which includes secretion of IL-33 by endothelial cells and astrocytes. (3) IL-33 is known to interact with a heterodimeric complex comprised of ST2 and IL-1RAcP, which are coupled to both NF-κB and P38 MAPK signaling pathways, ultimately driving the expression of other cytokines and chemokines. (4) It should be noted that ST2 can also be released from cells in soluble form, where it serves to inactivate extracellular IL-33 by serving as a decoy receptor. (5) IL-33 may impact MDD risk directly by modulating neuronal circuits responsible for affect regulation, or (6) indirectly by promoting the expression of other key cytokines/chemokines known to moderate MDD risk.