miR-155 Deficiency Ameliorates Autoimmune Inflammation of Systemic Lupus Erythematosus by Targeting S1pr1 in Faslpr/lpr Mice.
MicroRNA-155 (miR-155) was previously found involved in the development of systemic lupus erythematosus (SLE) and other autoimmune diseases and the inflammatory response; however, the detailed mechanism of miR-155 in SLE is not fully understood. To explore the in vivo role of miR-155 in the pathogenesis of SLE, miR-155-deficient Fas(lpr/lpr) (miR-155(-/-)Fas(lpr/lpr)) mice were obtained by crossing miR-155(-/-) and Fas(lpr/lpr) mice. Clinical SLE features such as glomerulonephritis, autoantibody levels, and immune system cell populations were compared between miR-155(-/-)Fas(lpr/lpr) and Fas(lpr/lpr) mice. Microarray analysis, RT-PCR, Western blot, and luciferase reporter gene assay were used to identify the target gene of miR-155. miR-155(-/-)Fas(lpr/lpr) mice showed milder SLE clinical features than did Fas(lpr/lpr)mice. As compared with Fas(lpr/lpr) mice, miR-155(-/-)Fas(lpr/lpr) mice showed less deposition of total IgA, IgM, and IgG and less infiltration of inflammatory cells in the kidney. Moreover, the serum levels of IL-4 and IL-17a, secreted by Th2 and Th17 cells, were lower in miR-155(-/-)Fas(lpr/lpr) than Fas(lpr/lpr) mice; the CD4(+)/CD8(+) T cell ratio was restored in miR-155(-/-)Fas(lpr/lpr) mice as well. Sphingosine-1-phosphate receptor 1 (S1PR1) was found as a new target gene of miR-155 by in vitro and in vivo studies; its expression was decreased in SLE patients and Fas(lpr/lpr) mice. miR-155(-/-)Fas(lpr/lpr) mice are resistant to the development of SLE by the regulation of the target gene S1pr1. miR-155 might be a new target for therapeutic intervention in SLE.
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Qian
Q
Xin
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Jiangxia
J
Li
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Jie
J
Dang
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Xianli
X
Bian
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Shan
S
Shan
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Jupeng
J
Yuan
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Yanyan
Y
Qian
Department of Cell Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China; and.
Zhaojian
Z
Liu
Department of Nephrology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
Guangyi
G
Liu
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Qianqian
Q
Yuan
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Na
N
Liu
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Xiaochun
X
Ma
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Fei
F
Gao
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China;
Yaoqin
Y
Gong
Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Medical Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China; liuqiji@sdu.edu.cn.
Qiji
Q
Liu
D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D016516:CD4-CD8 Ratio; D002460:Cell Line; D015536:Down-Regulation; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000235:genetics*; D000081025:Sphingosine-1-Phosphate Receptors; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D019014:fas Receptor / Q000235:genetics
D001323:Autoantibodies; C491899:Fas protein, mouse; C098680:Il17a protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D020381:Interleukin-17; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D019014:fas Receptor; D015847:Interleukin-4