Interferon Regulatory Factor 5 Is Critical for the Development of Lupus in MRL/lpr Mice
Interferon Regulatory Factor 5 Is Critical for the Development of Lupus in MRL/lpr Mice
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DOI：
10.1002/art.30183
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发表时间：
2011-03-01
影响因子：
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通讯作者：
Nagasawa, Kohei
中科院分区：
文献类型：
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作者：
Tada, Yoshifumi;Kondo, Seiji;Nagasawa, Kohei
Objective.干扰素调节因子5（IRF-5）是一种转录因子，介导由Toll样受体（TLR）激活的细胞内信号。IRF 5多态性与不同人群中系统性红斑狼疮（SLE）风险的增加或减少相关，但IRF 5在SLE发展中的确切作用尚未完全了解。本研究旨在探讨IRF 5在小鼠狼疮发生发展中的作用。我们将基因靶向IRF 5缺陷（IRF 5（-/-））小鼠与MRL/MpJ-lpr/lpr（MRL/lpr）小鼠杂交，并检查后代的存活率、肾小球肾炎、自身抗体水平、免疫系统细胞群和树突状细胞功能。IRF 5（-/-）MRL/lpr小鼠比对照IRF 5（+/+）MRL/lpr小鼠存活时间更长，并且仅显示非常轻度的肾小球肾炎。IRF 5（-/-）MRL/lpr小鼠血清中SLE相关核抗原的自身抗体较低，脾脏中活化的CD 4（+）T细胞数量减少。当用TLR-7或TLR-9配体或免疫复合物体外处理时，来自IRF 5（-/-）MRL/lpr小鼠的脾DC产生较低水平的炎性细胞因子。干扰素-α的产生对CpG的反应也减少。我们的研究结果表明，IRF 5是小鼠狼疮发展的关键驱动因素，并表明IRF 5可能是控制SLE患者疾病的治疗干预的一个有吸引力的新靶点。
Objective. Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus.Methods. We crossed gene-targeted IRF5-deficient (IRF5(-/-)) mice with MRL/MpJ-lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function.Results. IRF5(-/-)MRL/lpr mice survived longer than control IRF5(+/+)MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE-related nuclear antigens were lower in IRF5(-/-)MRL/lpr mouse serum, and numbers of activated CD4(+) T cells were reduced in the spleen. Splenic DCs from IRF5(-/-) MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-alpha production in response to CpG was also decreased.Conclusion. Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.