ID: 114: Molecular determinants of agonist and antagonist signaling through the IL-36 receptor

Abstract

The IL-1 family consists of 11 cytokines that control a complex network of pro-inflammatory signals. They also play a central role in numerous chronic inflammatory disorders and, accordingly, inhibition of these cytokines is an important therapeutic strategy. Agonist cytokines in the IL-1 family signal by binding their cognate receptor, followed by recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of the co-receptor, precluding signaling. The IL-36 subfamily is the most diverse, including three agonists and one antagonist (IL-36Ra), yet least well characterized group within this family. Recently, IL-38 has been reported to act as another antagonist for the IL-36 receptor, IL-36R. Well balanced IL-36 signaling is a critical determinant of skin health and IL-36 can stimulate DCs and prime naive CD4 T cells for Th1 responses. IL-36 signaling has been presumed to function analogously to IL-1. Here, we have defined molecular determinants of agonist and antagonist signaling through IL-36R. We present the first crystal structure of an IL-36 agonist (IL-36gamma). Guided by this structure, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to and signaling through its receptor. Moreover, we solved the crystal structure of IL-38. Contrary to recent reports, we show that it does not directly interact with IL-36R and, instead, may be an agonist for the IL-33 receptor, ST2. Our data reveal that the fine specificity of IL-36 signaling is distinct from IL-1 and that IL-38 is not a classical IL-36R antagonist.