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Endothelial cell sphingosine 1-phosphate receptor 1 restrains VE-cadherin cleavage and attenuates experimental inflammatory arthritis.
Burg, Nathalie; Malpass, Ryan; Alex, Linda; Tran, Miles; Englebrecht, Eric; Kuo, Andrew; Pannelini, Tania; Minett, Margaret; Athukorala, Kalana; Worgall, Tilla; Faust, Heather J; Goodman, Susan; Mehta, Bella; Brenner, Michael; Vestweber, Dietmar; Wei, Kevin; Blobel, Carl; Hla, Timothy; Salmon, Jane E.
Afiliación
  • Burg N; Hospital for Special Surgery, New York, New York, USA.
  • Malpass R; Hospital for Special Surgery, New York, New York, USA.
  • Alex L; Hospital for Special Surgery, New York, New York, USA.
  • Tran M; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Englebrecht E; School of Medicine, University of Louisville, Louisville, Kentucky, USA.
  • Kuo A; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
  • Pannelini T; Hospital for Special Surgery, New York, New York, USA.
  • Minett M; Hospital for Special Surgery, New York, New York, USA.
  • Athukorala K; University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
  • Worgall T; Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
  • Faust HJ; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Goodman S; Hospital for Special Surgery, New York, New York, USA.
  • Mehta B; Hospital for Special Surgery, New York, New York, USA.
  • Brenner M; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Vestweber D; Max Planck Institute, Munster, Germany.
  • Wei K; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Blobel C; Hospital for Special Surgery, New York, New York, USA.
  • Hla T; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
  • Salmon JE; Hospital for Special Surgery, New York, New York, USA.
JCI Insight ; 9(11)2024 Jun 10.
Article en En | MEDLINE | ID: mdl-38855867
ABSTRACT
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 the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Experimental / Artritis Reumatoide / Antígenos CD / Cadherinas / Células Endoteliales / Proteína ADAM10 / Receptores de Esfingosina-1-Fosfato Límite: Animals / Female / Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Artritis Experimental / Artritis Reumatoide / Antígenos CD / Cadherinas / Células Endoteliales / Proteína ADAM10 / Receptores de Esfingosina-1-Fosfato Límite: Animals / Female / Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos