Endothelial IL-1R1 is a critical mediator of EAE pathogenesis.
Interleukin-1 (IL-1) has been implicated in the disease progression of multiple sclerosis (MS). In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the induction of disease is significantly attenuated in mice lacking the type I IL-1 receptor (IL-1R1). In this study, we created a transgenic mouse (eIL-1R1 kd) in which IL-1R1 expression is knocked down specifically in endothelial cells. Induction of EAE in eIL-1R1 kd mice results in a decrease in incidence, severity and delayed onset of EAE. In addition, eIL-1R1 kd mice show significant decrease in VCAM-1 expression and diminished CD45(+) and CD3(+) infiltrating leukocytes in the spinal cord in animals challenged with EAE. Further, IL-1 and IL-23 stimulate IL-17 production by splenocytes from both wild type and the eIL-1R1 kd animals. Similarly, IL-1 and IL-23 synergistically stimulate splenocytes proliferation in these two strains of animals. After immunization with MOG(79-96), although eIL-1R1 kd mice displayed greatly reduced clinical scores, their splenocytes produced IL-17 and proliferated in response to a second MOG challenge, similar to wild type animals. These findings indicate a critical role for endothelial IL-1R1 in mediating the pathogenesis of EAE, and describe a new model that can be used to study endothelial IL-1R1.
Li
Qiming
Q
Institute of Behavior Medicine, 3132 Postle Hall, 305 West 12th Avenue, Ohio State University, Columbus, OH 43210-1094, USA.
Powell
Nicole
N
Zhang
Hao
H
Belevych
Natalya
N
Ching
San
S
Chen
Qun
Q
Sheridan
John
J
Whitacre
Caroline
C
Quan
Ning
N
D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D004730:Endothelium, Vascular / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D007114:Immunization; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology; D053759:Interleukin-23 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D051379:Mice; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000235:genetics / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D053573:Receptors, Interleukin-1 Type I / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018076:DNA, Complementary; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D012333:RNA, Messenger; D053573:Receptors, Interleukin-1 Type I; D019010:Vascular Cell Adhesion Molecule-1; D049452:Green Fluorescent Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D017493:Leukocyte Common Antigens