Interleukin-36: Structure, Signaling and Function.

The IL-36 family belongs to a larger IL-1 superfamily and consists of three agonists (IL-36α/β/γ), one antagonist (IL-36Ra), one cognate receptor (IL-36R) and one accessory protein (IL-1RAcP). The receptor activation follows a two-step mechanism in that the agonist first binds to IL-36R and the resulting binary complex recruits IL-1RAcP. Assembled ternary complex brings together intracellular TIR domains of receptors which activate downstream NF-κB and MAPK signaling. Antagonist IL-36Ra inhibits the signaling by binding to IL-36R and preventing recruitment of IL-1RAcP. Members of IL-36 are normally expressed at low levels. Upon stimulation, they are inducted and act on a variety of cells including epithelial and immune cells. Protease mediated N-terminal processing is needed for cytokine activation. In the skin, the functional role of IL-36 is to contribute to host defense through inflammatory response. However, when dysregulated, IL-36 stimulates keratinocyte and immune cells to enhance the Th17/Th23 axis and induces psoriatic-like skin disorder. Genetic mutations of the antagonist IL-36Ra are associated with occurrence of generalized pustular psoriasis, a rare but life-threatening skin disease. Anti-IL-36 antibodies attenuate IMQ or IL-23 induced skin inflammation in mice, illustrating IL-36's involvement in mouse model of psoriasis. Other organs such as the lungs, the intestine, the joints and the brain also express IL-36 family members upon stimulation. The physiological and pathological roles of IL-36 are less well defined in these organs than in the skin. In this chapter, current progress on IL-36 protein and biology is reviewed with a discussion on investigative tools for this novel target.