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bioRxiv · 10.1101/2025.02.22.639629

Structural basis of pro-inflammatory signaling via the Interleukin-36 receptor (IL-36R) mediated by IL-36γ and IL-37

Andries, J.·Toul, M.·Felix, J.·Clancy, D. M.·Savvides, S. N.
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Abstract

Interleukin-36 receptor (IL-36R) is activated by IL-36, IL-36{beta}, and IL-36{gamma} to elicit pro-inflammatory signaling and is targeted in acute skin inflammation by the approved antibody spesolimab. IL-37 was recently proposed as a new IL-36R agonist. Such diverse agonist repertoire together with the antagonistic IL-36Ra and IL-38 create a fascinating structure-function landscape for IL-36R, albeit one that is poorly understood. Here, we elucidate how IL-36R grapples IL-36{gamma} with low affinity to enable facile recruitment of the shared receptor IL-1RAcP with high-affinity. In contrast, IL-36R interacts with IL-37 via the exact opposite binding signature. Comparative interrogation of IL-36R activation by IL-36{gamma} and IL-37 confirmed their common pro-inflammatory signature and distinguished IL-36{gamma} as markedly more pro-inflammatory. Structural comparisons of cytokine-activated versus spesolimab-antagonized IL-36R revealed spesolimabs mode of action as an allosteric antagonist. Collectively, our study provides the structural and mechanistic blueprint of IL-36R activation by distinct cytokines and will facilitate its therapeutic targeting. One Sentence SummaryStructural blueprint for IL-36R activation by cognate cytokines and its antagonism by spesolimab in generalized pustular psoriasis.

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Andries, J., Toul, M., Felix, J., Clancy, D. M., Savvides, S. N.. 2025-02-27. Structural basis of pro-inflammatory signaling via the Interleukin-36 receptor (IL-36R) mediated by IL-36γ and IL-37. https://doi.org/10.1101/2025.02.22.639629

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