Costunolide targets USP15 to suppress TNF-α-induced retinal inflammation, ameliorating autoimmune uveitis

Autoimmune uveitis is a severe, sight-threatening inflammatory disease primarily driven by excessive leukocyte infiltration into the retina. A critical early event in this pathology is the activation of retinal vascular endothelial cells (ECs), which then up-regulate adhesion molecules, facilitating T cell adhesion and subsequent extravasation into ocular tissues. Current treatments, while addressing some aspects like vascular permeability (e.g., anti-VEGF therapies), often fall short in effectively controlling this initial, critical inflammatory cascade and leukocyte trafficking, leaving a significant therapeutic gap for early disease intervention.

Researchers identified the small terpenoid compound costunolide (COS) as a potent suppressor of retinal endothelial inflammation. They performed quantitative proteomics on primary human retinal endothelial cells (ECs) stimulated with TNF-α to define a proinflammatory endothelial signature. A focused library of 337 terpenoids was screened to identify compounds that attenuated TNF-α-induced endothelial activation. In vivo, COS was administered to an experimental autoimmune uveitis (EAU) model to assess its impact on disease progression, endothelial adhesion molecule expression, and T cell infiltration. Mechanistic studies investigated COS's direct targets and its effect on TNF signaling.

Stimulation of human retinal ECs with TNF-α induced a distinct proinflammatory endothelial signature, including the up-regulation of adhesion molecules. Screening revealed costunolide (COS) as a top hit, markedly attenuating TNF-α-induced endothelial activation. > In vivo, COS treatment significantly reduced both clinical and histopathologic EAU scores, demonstrating its therapeutic efficacy in a relevant disease model. This improvement was accompanied by reduced endothelial adhesion molecule expression and a decreased infiltration of T cells into the retina. Mechanistically, COS directly targeted the deubiquitinase USP15, inhibiting USP15-dependent deubiquitination of TRAF1 and subsequently suppressing TNF signaling within retinal ECs. These findings establish a novel TNF-α-USP15-TRAF1 axis in retinal endothelium.