Endothelial cell sphingosine 1-phosphate receptor 1 restrains VE-cadherin cleavage and attenuates experimental inflammatory arthritis

• DOI: 10.1172/jci.insight.171467
• Publication Date: 2024-06-09T18:00:27Z
• Authors: Nathalie Burg; Ryan Malpass; Linda Alex; Miles Tran; Eric Englebrecht; Andrew Kuo; Tania Pannelini; Margaret Minett; Kalana Athukorala; Tilla Worgall; Heather J. Faust; Susan Goodman; Bella Mehta; Michael Brenner; Dietmar Vestweber; Kevin Wei; Carl Blobel; Timothy Hla; Jane E. Salmon
• Keywords: S1PR1; VE-cadherin; ADAM10; Vascular permeability

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains vascular barrier. Here, we assessed integrity and EC S1PR1 signaling to joint damage in mice exposed serum-induced arthritis (SIA). EC-specific deletion or pharmacological blockade promoted leak amplified SIA, whereas overexpression treatment with an agonist delayed SIA. Blockade induced membrane metalloproteinase-dependent cleavage cadherin (VE-cadherin), a principal adhesion molecule that junctional integrity. We identified disintegrin metalloproteinase domain 10 (ADAM10) as VE-cadherin "sheddase." Mice expressing stabilized construct had decreased extravascular leakage response blockade, they were protected Importantly, patients active circulating S1P microvascular expression S1PR1, suggesting dysregulated S1P/S1PR1 axis favoring permeability vulnerability. present model which homeostatic barrier function by limiting shedding mediated ADAM10 suggest this therapeutic target arthritis.