IL-17 Signaling Mediates Inflammation-Induced Capillary Leakage in addition to TNFa

Capillary leak is a hallmark of acute and chronic inflammatory conditions and represents a critical driver of organ dysfunction and poor clinical outcomes. Despite its clinical relevance, the mechanisms governing endothelial destabilization under inflammatory conditions remain incompletely understood. In this study, we investigated the endothelial response to inflammation using a dynamic human in vitro model, in which human umbilical vein endothelial cells (HUVECs) were cultured in the presence of lipopolysaccharide (LPS)–stimulated human peripheral blood mononuclear cells (PBMCs) to mimic systemic inflammation. Under these conditions, endothelial cells exhibited a pronounced inflammatory response characterized by loss of barrier integrity and the formation of capillary leak–like structures. Separated transcriptomic pathway analyses of HUVECs and PBMCs identified a strong activation of cytokine-driven signalling networks, with the IL-17 pathway emerging as a dominant regulator of endothelial dysfunction, alongside TNF and JAK–STAT signalling. Targeted pharmacological inhibition demonstrated that blockage of IL-17 signalling most effectively stabilized the endothelial layer and mitigated leak-like morphology compared to inhibition of other pathways. However, endothelial barrier function was only partially restored, indicating persistent dysfunction despite IL-17 pathway suppression. Together, these findings position IL-17 as a key driver of inflammation-induced capillary leak while highlighting the multifactorial nature of endothelial destabilization. This work underscores the necessity of addressing complex immune–endothelial interactions to develop effective strategies for preventing inflammation-induced vascular leakage.