Investigating and exploiting the "moonlighting" functions of interleukin-1α (IL-1α) for activity regulation

• Applicants: Professor Dr. Emmanuel Ampofo-Wilhelm; Professorin Dr. María Teresa Pisabarro; Professorin Dr. Sandra Rother
• Subject Area: Cell Biology ; Bioinformatics and Theoretical Biology ; Immunology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575188479

Interleukin-1α (IL-1α) is a unique dual-function cytokine involved in inflammation and tissue repair. Beyond its classical role as a pro-inflammatory alarmin, IL-1α also exhibits non-canonical, “moonlighting” functions. Recent work from our group uncovered that IL-1α is expressed on the monocyte surface, where it facilitates adhesion to the endothelium, and that glycosaminoglycans (GAGs), key components of the endothelial glycocalyx, enhance IL-1α signaling. Preliminary data indicate that IL-1α directly binds heparan sulfate (HS) and chondroitin sulfate (CS), and that its receptor IL-1R1 also interacts with GAGs. We hypothesize that GAGs function as molecular bridges that modulate the IL-1α/GAG/IL-1R1 axis, thereby regulating leukocyte-endothelial interactions and inflammatory signaling. Additionally, we identified IL-1α as a novel regulator of GAG biosynthesis in a genome-wide CRISPR-Cas9 screen, an effect not observed for IL-1β, indicating an IL-1R-independent, nuclear role of IL-1α. Our data suggest that nuclear pro-IL-1α promotes GAG synthesis and endothelial glycocalyx restoration, potentially contributing to inflammation resolution. This positions IL-1α as both a pro-inflammatory mediator and a promoter of endothelial homeostasis, depending on its cellular localization and interaction context. This project aims to systematically dissect the molecular mechanisms by which IL-1α governs leukocyte-endothelial interactions and glycocalyx dynamics. Specifically, we will (1) define GAG/IL-1α and GAG/IL-1R1 interaction profiles and their impact on endothelial signaling; (2) elucidate nuclear IL-1α-dependent regulation of GAG biosynthetic enzymes and its role in glycocalyx recovery; and (3) develop peptidomimetic compounds targeting the IL-1α pathway as proof-of-concept therapeutics. This multidisciplinary approach combines in silico, in vitro and in vivo models, and de novo rational drug design. By unveiling the dual functions of IL-1α in inflammation and tissue repair, this project will not only provide novel mechanistic insights into endothelial immunobiology but also lay the groundwork for innovative therapeutic strategies targeting IL-1α in inflammatory diseases.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Gloria Ruiz Gómez