2025-04-112025-04-112024Rodríguez Hernández, M.A., Baena Bustos, M., Carneros, D., Zurita Palomo, C., Muñoz Pinillos, P., Millán, J.,...,Bustos, M. (2024). Targeting IL-6 Trans-signalling by sgp130Fc Attenuates Severity in SARS-CoV-2 -Infected Mice and Reduces Endotheliopathy. eBioMedicine, 103, 105132. https://doi.org/10.1016/j.ebiom.2024.105132.2352-3964https://hdl.handle.net/11441/171750Background: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. Methods: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. Findings: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. Interpretation: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19.application/pdf17 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/COVID-19EndotheliopathyIL-6 trans-signallingK18-hACE2 transgenic miceSARS-CoV-2sgp130Fcinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccess10.1016/j.ebiom.2024.105132