ACR Meeting Abstracts

ACR Meeting Abstracts

  • Meetings
    • ACR Convergence 2024
    • ACR Convergence 2023
    • 2023 ACR/ARP PRSYM
    • ACR Convergence 2022
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • ACR Meetings

Abstract Number: 1790

Sphingosine -1 Phosphate Receptor-1-Mediated Endothelial Cell Barrier Function Protects Against Immune Complex-Induced Vascular Injury: A Potential Novel Therapeutic Target for SLE

Nathalie Burg1, Steven Swendeman2, Stefan Worgall3, Timothy Hla2 and Jane E. Salmon1, 1Rheumatology, Hospital for Special Surgery, New York, NY, 2Boston Children's Hospital, Boston, MA, 3Pediatrics/ Pulmonary, Weill Cornell Medical Center, New York, NY

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Inflammation

  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print
Session Information

Date: Monday, November 6, 2017

Title: Cytokines, Mediators, Cell-Cell Adhesion, Cell Trafficking and Angiogenesis: Unexpected Effects from "Well-Known" Molecules

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:

Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid, is important for vascular homeostasis via signaling through S1P receptors. HDL-bound apolipoprotein M (ApoM) is a physiological S1P carrier that activates endothelial S1P1 receptors, thereby increasing barrier function. ApoM-S1P also limits endothelial cell expression of adhesion molecules and activation of NF-κB in response to TNF-α. We tested a novel biologic S1P1 receptor agonist, ApoM-Fc loaded with S1P, for its ability to protect the endothelial barrier in response to immune complex (IC) and neutrophil (PMN)-mediated injury in vitro and in vivo.

Methods:

Barrier function of human umbilical vein endothelial cells (HUVECs) in response to IC and C5a activated PMNs +/- ApoM-Fc was assessed by Electric Cell-substrate Impedance Sensing (ECIS). Phosphorylation of myosin light chain2 (p-MLC2) and VE-Cadherin staining in HUVECs after treatment with activated PMNs +/- ApoM-Fc was assessed by immunofluorescence (IF). The reverse arthus reaction (RAR) was performed in skin in mice treated locally with S1P1 agonists and antagonists. Lung RAR was performed in WT and Apom-/- mice and mice with an inducible endothelial cell deletion of S1P1 (ECKO). ApoM-Fc (100 μg, IP) or PBS was administered to WT mice 2 hrs before lung RAR. PMNs and red blood cells in bronchoalveolar lavage fluid (BALF) were quantified. Lung weights and Evans blue (EB) were measured.

Results:

Activated PMNs decreased HUVEC resistance in ECIS and increased p-MLC2 and VE-Cadherin junction disassembly as assessed by IF. ApoM-Fc prevented the loss of barrier function (mean increase 224±28 Ohms, n=4) in a sustained manner (>8 hrs) and markedly reduced PMN-induced p-MLC2 and loss of VE-Cadherin. In contrast, a mutated ApoM-Fc construct that does not bind S1P was not protective. S1P also attenuated IC-mediated injury in vivo. S1P1 agonist CYM-5442 decreased EB leak and skin weights after RAR compared to PBS treated controls (20 vs 27 mg, n=15-20, p <0.0001) and W146, a S1P1 antagonist, increased EB leak and skin weights after RAR (24 vs 21 mg, n=12; p= 0.02). S1P1 ECKO mice showed markedly increased lung RAR compared to controls: EB extravasation (157 vs 95 µg/g, n=3-5 mice; p=0.04), BAL WBCs (1.0 vs 0.6 X103/µl, n=8-11; p=0.03), and lung mass (330 vs 265 mg, n=5-6; p=0.0007). Apom-/- treated with local administration of W146 to partially block S1P1 also showed more intense lung RAR than WT controls treated with W146, consistent with increased vascular vulnerability to injury. Importantly, delivery of S1P in vivo with ApoM-Fc was able to limit lung RAR with reduction in BALF WBCs and RBCs and decreased extravasated EB compared to PBS treated controls.

Conclusion:

These data demonstrate that stimulation of endothelial S1P1 receptor by ApoM-HDL-S1P protects barrier integrity of the microvessels when challenged by IC-mediated vascular injury. S1P1 receptor agonism represents a novel target to limit inflammation-induced injury in SLE and other IC mediated diseases. Moreover, because ApoM-Fc does not induce lymphopenia, unlike most other S1P1 agonists, it could be used concomitantly with immunosuppressive therapies.


Disclosure: N. Burg, None; S. Swendeman, None; S. Worgall, None; T. Hla, None; J. E. Salmon, None.

To cite this abstract in AMA style:

Burg N, Swendeman S, Worgall S, Hla T, Salmon JE. Sphingosine -1 Phosphate Receptor-1-Mediated Endothelial Cell Barrier Function Protects Against Immune Complex-Induced Vascular Injury: A Potential Novel Therapeutic Target for SLE [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/sphingosine-1-phosphate-receptor-1-mediated-endothelial-cell-barrier-function-protects-against-immune-complex-induced-vascular-injury-a-potential-novel-therapeutic-target-for-sle/. Accessed .
  • Tweet
  • Click to email a link to a friend (Opens in new window) Email
  • Click to print (Opens in new window) Print

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/sphingosine-1-phosphate-receptor-1-mediated-endothelial-cell-barrier-function-protects-against-immune-complex-induced-vascular-injury-a-potential-novel-therapeutic-target-for-sle/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

Accepted abstracts are made available to the public online in advance of the meeting and are published in a special online supplement of our scientific journal, Arthritis & Rheumatology. Information contained in those abstracts may not be released until the abstracts appear online. In an exception to the media embargo, academic institutions, private organizations, and companies with products whose value may be influenced by information contained in an abstract may issue a press release to coincide with the availability of an ACR abstract on the ACR website. However, the ACR continues to require that information that goes beyond that contained in the abstract (e.g., discussion of the abstract done as part of editorial news coverage) is under media embargo until 10:00 AM ET on November 14, 2024. Journalists with access to embargoed information cannot release articles or editorial news coverage before this time. Editorial news coverage is considered original articles/videos developed by employed journalists to report facts, commentary, and subject matter expert quotes in a narrative form using a variety of sources (e.g., research, announcements, press releases, events, etc.).

Violation of this policy may result in the abstract being withdrawn from the meeting and other measures deemed appropriate. Authors are responsible for notifying colleagues, institutions, communications firms, and all other stakeholders related to the development or promotion of the abstract about this policy. If you have questions about the ACR abstract embargo policy, please contact ACR abstracts staff at [email protected].

Wiley

  • Online Journal
  • Privacy Policy
  • Permissions Policies
  • Cookie Preferences

© Copyright 2025 American College of Rheumatology