Inhibition of Sphingosine-1-phosphate receptors in ischemia reperfusion injured autoimmunity-prone mice.
B6.MRL/lpr mice, an autoimmune strain, have an accelerated injury time course, increased intensity of tissue damage, and increased CD4+ T cell infiltration in the mesenteric ischemia/reperfusion injury model. In this study, the mechanism by which CD4+ T cells were recruited into injured tissue was addressed. Fingolimod (FTY720) was utilized to assess the role of infiltrating CD4+ T cells. FTY720 treatment was more effective in attenuating injury in B6.MRL/lpr mice then in control mice. Reduced CD4+ cell infiltration and tissue injury correlated with decreased neutrophil infiltration and pro-inflammatory cytokine generation. Inhibiting downstream Sphingosine-1-phosphate (S1P) receptor signaling, specifically GαI mediated signaling, did not inhibit injury, suggesting differential utilization of the S1P receptors between control and MRL/lpr strains. Analysis of S1P receptor expression exposed a predominance of S1P2 in the B6.MRL/lpr strain. Reliance on alternate S1P receptors in the autoimmune strain will alter the progress of inflammation and tissue injury.
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Jess
J
Edison
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Sharon
S
Frattalone
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Christopher
C
Tracy
Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Geoffrey E
GE
Woodard
Walter Reed National Military Medical Center, Bethesda, MD, USA.
Melissa
M
Butts
Department of Medicine, Uniformed Services University for the Health Sciences, Bethesda, MD, USA. Electronic address: Chantal.Moratz@usuhs.edu.
C M
CM
Moratz
D000818:Animals; D015551:Autoimmunity; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009504:Neutrophils / Q000276:immunology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology; D000081025:Sphingosine-1-Phosphate Receptors
D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; D000068876:Fingolimod Hydrochloride
Autoimmunity; Inflammation: tissue injury T cells; Sphingosine-1-phosphate