Endothelial IL-36 receptor activation promotes vascular stability to limit pathological microvessel permeability in the CNS

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Pathological increases in vascular permeability cause edema and swelling, driving retinal and neurological disorders. Few factors are known to specifically enhance barrier integrity and prevent fluid leakage. Here, we examine the effects of IL-36 receptor (IL-36R) activation on vascular permeability in vivo in mice, ex vivo in tissue explants, and in vitro in primary mouse and human microvascular endothelial cells. Using a soluble, biologically active DEVD-modified recombinant IL-36β cytokine, we find that the processed DEVD IL-36β strengthens endothelial barrier function, reduces vascular leakage, and limits pathology. Cell-specific knockdown of IL-36R confirms that endothelial IL-36R signaling mediates these barrier-promoting effects. IL-36R localizes to the plasma membrane in response to the loss of endothelial cell-cell contact, consistent with its role in tissue stress responses. Mechanistically, IL-36R signaling enhances adherens and tight junctions, induces vasculoprotective processes, and drives vessel remodeling and stabilization. RNA sequencing supports these findings, establishing IL-36R as a regulator of vascular integrity.