Sphingosine 1-Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex-Induced Vascular Injury

Arthritis Rheumatol. 2018 Nov;70(11):1879-1889. doi: 10.1002/art.40558.


Objective: Immune complex (IC) deposition activates polymorphonuclear neutrophils (PMNs), increases vascular permeability, and leads to organ damage in systemic lupus erythematosus and rheumatoid arthritis. The bioactive lipid sphingosine 1-phosphate (S1P), acting via S1P receptor 1 (S1P1 ), is a key regulator of endothelial cell (EC) barrier function. This study was undertaken to investigate whether augmenting EC integrity via S1P1 signaling attenuates inflammatory injury mediated by ICs.

Methods: In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVECs) by electrical cell-substrate impedance sensing. Phosphorylation of myosin light chain 2 (p-MLC-2) and VE-cadherin staining in HUVECs were assessed by immunofluorescence. A reverse Arthus reaction (RAR) was induced in the skin and lungs of mice with S1P1 deleted from ECs (S1P1 EC-knockout [ECKO] mice) and mice treated with S1P1 agonists and antagonists.

Results: S1P1 agonists prevented loss of barrier function in HUVECs treated with IC-activated PMNs. S1P1 ECKO and wild-type (WT) mice treated with S1P1 antagonists had amplified RAR, whereas specific S1P1 agonists attenuated skin and lung RAR in WT mice. ApoM-Fc, a novel S1P chaperone, mitigated EC cell barrier dysfunction induced by activated PMNs in vitro and attenuated lung RAR. Expression levels of p-MLC-2 and disruption of VE-cadherin, each representing manifestations of cell contraction and destabilization of adherens junctions, respectively, that were induced by activated PMNs, were markedly reduced by treatment with S1P1 agonists and ApoM-Fc.

Conclusion: Our findings indicate that S1P1 signaling in ECs modulates vascular responses to IC deposition. S1P1 agonists and ApoM-Fc enhance the EC barrier, limit leukocyte escape from capillaries, and provide protection against inflammatory injury. The S1P/S1P1 axis is a newly identified target to attenuate tissue responses to IC deposition and mitigate end-organ damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Anilides / pharmacology
  • Animals
  • Antigen-Antibody Complex / metabolism*
  • Antigens, CD / drug effects
  • Antigens, CD / metabolism
  • Apolipoproteins M / pharmacology
  • Arthus Reaction
  • Cadherins / drug effects
  • Cadherins / metabolism
  • Capillary Permeability / drug effects
  • Capillary Permeability / genetics*
  • Cardiac Myosins / drug effects
  • Cardiac Myosins / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Indans / pharmacology
  • Lung / blood supply
  • Lung / drug effects
  • Lung / metabolism
  • Lysophospholipids / pharmacology
  • Mice
  • Mice, Knockout
  • Myosin Light Chains / drug effects
  • Myosin Light Chains / metabolism
  • Organophosphonates / pharmacology
  • Oxadiazoles / pharmacology
  • Receptors, Lysosphingolipid / agonists
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Receptors, Lysosphingolipid / genetics*
  • Receptors, Lysosphingolipid / metabolism
  • Skin / blood supply
  • Skin / drug effects
  • Skin / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Sphingosine-1-Phosphate Receptors
  • Thiophenes / pharmacology


  • 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol
  • 3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid
  • Anilides
  • Antigen-Antibody Complex
  • Antigens, CD
  • Apolipoproteins M
  • Cadherins
  • Indans
  • Lysophospholipids
  • Myosin Light Chains
  • Organophosphonates
  • Oxadiazoles
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • S1pr1 protein, mouse
  • SEW2871
  • Sphingosine-1-Phosphate Receptors
  • Thiophenes
  • cadherin 5
  • myosin light chain 2
  • sphingosine 1-phosphate
  • Cardiac Myosins
  • Sphingosine