The structural basis of IL-36R proinflammatory signaling mediated by IL-36γ and IL-37

The interleukin-36 receptor (IL-36R) drives proinflammatory signaling and is therapeutically targeted by spesolimab in acute skin inflammation. Beyond its three canonical agonists (IL-36α, IL-36β, and IL-36γ), IL-36R was recently proposed to be activated by IL-37. Together with antagonism by IL-36R antagonist (IL-36RA) and IL-38, this creates a complex structure-function landscape that remains poorly understood. Here, we report the cryo-electron microscopy (cryo-EM) structure of human IL-36γ bound to IL-36R and the shared co-receptor IL-1R accessory protein (IL-1RAcP). IL-36γ engages IL-36R with low affinity, enabling high-affinity IL-1RAcP recruitment. IL-37 exhibits the opposite binding signature, binding IL-36R with high affinity but IL-1RAcP weakly. Functional comparison of IL-36R engagement by IL-36γ and IL-37 confirmed their common proinflammatory signature, with IL-36γ exhibiting markedly higher potency, consistent with its more stable signaling complex. Structural comparison of cytokine-bound versus antibody-antagonized IL-36R revealed that spesolimab acts as an allosteric antagonist. This study therefore provides a structural and mechanistic blueprint for IL-36R activation by distinct cytokines.