Andries, J. | bioRxiv Science

bioRxiv2025

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

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.

immunology↗

bioRxiv2022

Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein (IL-18BP) in inflammation and tumor immunity

Human Interleukin-18 (IL-18) is an omnipresent pro-inflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases, and serving as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase in COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18 Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors would be highly desirable. However, the structure of human IL-18BP in complex with IL-18 had remained elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP towards IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecule from different complexes, resulting in a novel complex with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings will provide a framework for innovative structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease. Significance statementElevated levels of interleukin-18 (IL-18) have long been implicated in numerous inflammatory diseases while also displaying potent anti-tumoral activities. Recent research on COVID-19 has now underscored the role of IL-18 and IL-18 binding protein (IL-18BP), a soluble receptor serving to regulate IL-18 activity, as key players in viral immunity and as promising biomarkers and predictors of disease severity. In this work, we present detailed structural insights into how human IL-18 and IL-18BP interact thereby completing the structural repertoire of IL-18 in complex with its cognate human receptors and viral decoy receptors. Our findings will support structure-based efforts to either disrupt or enhance the interactions of IL-18 with its cognate receptors for therapeutic purposes.

immunology↗