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.
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 lipidsphingosine 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.
Authors: Susan R Schwab; João P Pereira; Mehrdad Matloubian; Ying Xu; Yong Huang; Jason G Cyster Journal: Science Date: 2005-09-09 Impact factor: 47.728
Authors: U Baumann; J Köhl; T Tschernig; K Schwerter-Strumpf; J S Verbeek; R E Schmidt; J E Gessner Journal: J Immunol Date: 2000-01-15 Impact factor: 5.422
Authors: M J Lee; S Thangada; K P Claffey; N Ancellin; C H Liu; M Kluk; M Volpi; R I Sha'afi; T Hla Journal: Cell Date: 1999-10-29 Impact factor: 41.582
Authors: J G Garcia; F Liu; A D Verin; A Birukova; M A Dechert; W T Gerthoffer; J R Bamberg; D English Journal: J Clin Invest Date: 2001-09 Impact factor: 14.808
Authors: Tracy Stokol; Peter O'Donnell; Ling Xiao; Sara Knight; George Stavrakis; Marina Botto; Ulrich H von Andrian; Tanya N Mayadas Journal: J Exp Med Date: 2004-10-04 Impact factor: 14.307
Authors: Marko Roblek; Darya Protsyuk; Paul F Becker; Cristina Stefanescu; Christian Gorzelanny; Jesus F Glaus Garzon; Lucia Knopfova; Mathias Heikenwalder; Bruno Luckow; Stefan W Schneider; Lubor Borsig Journal: Mol Cancer Res Date: 2018-12-14 Impact factor: 5.852
Authors: Lichun Wang; Eleftheria Letsiou; Huashan Wang; Patrick Belvitch; Lucille N Meliton; Mary E Brown; Mounica Bandela; Jiwang Chen; Joe G N Garcia; Steven M Dudek Journal: Am J Physiol Lung Cell Mol Physiol Date: 2021-12-08 Impact factor: 5.464
Authors: Bi-Sen Ding; Dawei Yang; Steve L Swendeman; Christina Christoffersen; Lars B Nielsen; Scott L Friedman; Charles A Powell; Timothy Hla; Zhongwei Cao Journal: Dev Cell Date: 2020-06-15 Impact factor: 12.270
Authors: Edwin R Chilvers; Charlotte Summers; Kathleen R Bashant; Angel M Aponte; Davide Randazzo; Paniz Rezvan Sangsari; Alexander Jt Wood; Jack A Bibby; Erin E West; Arlette Vassallo; Zerai G Manna; Martin P Playford; Natasha Jordan; Sarfaraz Hasni; Marjan Gucek; Claudia Kemper; Andrew Conway Morris; Nicole Y Morgan; Nicole Toepfner; Jochen Guck; Nehal N Mehta; Mariana J Kaplan Journal: Ann Rheum Dis Date: 2020-09-28 Impact factor: 19.103