Science Immunology· 2026Q1
The structural basis of IL-36R proinflammatory signaling mediated by IL-36γ and IL-37
- 1citations
- Q1SCImago
- 2026year
Short summary
Structural analysis reveals IL-36γ binds IL-36R with low affinity to recruit IL-1RAcP, while IL-37 binds IL-36R with the opposite signature, with IL-36γ proving more pro-inflammatory.
AI-generated from the title and abstract; the full text is not read.
Key points
- IL-36γ binds IL-36R with low affinity, enabling facile recruitment of IL-1RAcP.
- IL-37 interacts with IL-36R via an opposite binding signature compared to IL-36γ.
- Both IL-36γ and IL-37 share a pro-inflammatory signaling signature, with IL-36γ being more potent.
- Spesolimab acts as an allosteric antagonist by binding to IL-36R.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Interleukin-36 receptor (IL-36R) is activated by IL-36α, IL-36β, and IL-36γ 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-36γ 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-36γ and IL-37 confirmed their common pro-inflammatory signature and distinguished IL-36γ as markedly more pro-inflammatory. Structural comparisons of cytokine-activated versus spesolimab-antagonized IL-36R revealed spesolimab’s 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 Summary Structural blueprint for IL-36R activation by cognate cytokines and its antagonism by spesolimab in generalized pustular psoriasis.
The authors' abstract, as published at the source. Science Immunology, 2026 · DOI ↗
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ImmunologyImmunology and Microbiology