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

Cryo-EM reveals that human IL-36γ forms a low-affinity IL-36R complex that strongly recruits IL-1RAcP, producing a markedly higher-potency proinflammatory signaling complex.

• Why it matters: IL-36R is a key driver of proinflammatory signaling and a therapeutic target in acute skin inflammation, but how IL-36γ, IL-37, IL-36RA, and IL-38 differentially activate or antagonize it is unclear.
• What they did: The authors determined the cryo-EM structure of human IL-36γ bound to IL-36R and IL-1RAcP, then compared IL-36R engagement and signaling potency between IL-36γ and IL-37, alongside cytokine-bound versus spesolimab-antagonized receptor structures.
• The result: IL-36γ and IL-37 share a common proinflammatory signaling signature, yet IL-36γ shows markedly higher potency, and spesolimab functions as an allosteric antagonist, enabling a mechanistic blueprint for IL-36R activation.

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