Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice
Protection against autoimmune nephritis in MyD88-deficient MRL/lpr mice
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DOI：
10.1002/art.22571
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发表时间：
2007-05-01
影响因子：
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通讯作者：
Harada, Mine
中科院分区：
文献类型：
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作者：
Sadanaga, Atsushi;Nakashima, Hitoshi;Harada, Mine
目标。目的探讨天然受体信号在狼疮性肾炎模型MRL/LPR小鼠自身免疫性肾炎发生发展中的作用。MyD88是一个关键的接头，参与除TLR-3以外的所有Toll样受体(TLR)的信号通路。因此，我们产生了MyD88基因敲除(MyD88-KO)MRL/LPR小鼠，并检测了它们肾脏的组织病理学变化、累积存活率、淋巴病变和脾肿大的程度、血清化学和免疫学参数。此外，为了明确MyD88非依赖途径在自身免疫性肾炎中的作用，我们给MyD88-KO MRL/IPR小鼠腹腔注射Poly(I-C)(每只小鼠50或100 Jig)或磷酸盐缓冲盐水，并检查它们的存活率以及组织病理学、血清学和免疫学参数。与野生型小鼠相比，MyD88-KO MRL/LPR小鼠寿命延长，无明显的自身免疫性肾炎发生。他们的肾脏没有表现出肾小球细胞的增殖或新月体的形成，同时系膜基质急剧减少。淋巴结病和脾肿大不太明显。MyD88-KO MRL/IPR小鼠血清抗双链DNA滴度和脾细胞产生细胞因子，包括干扰素-α、白介素12、白介素6和干扰素均显著降低。有趣的是，经MyD88非依赖TLR-3配体聚(I-C)治疗的MyD88-KO MRL/IPR小鼠表现出几乎完全恢复到野生型小鼠的特征，表现为新月体肾炎，血清抗dsDNA滴度显著升高，脾细胞分泌细胞因子增加。这些结果表明，依赖于MyD88和不依赖于MyD88的先天信号在MRL/IPR小鼠自身免疫性肾炎的发生发展中起着关键作用。
Objective. To determine whether innate receptor signals play an important role in the development of autoimmune nephritis in MRL/lpr mice, an experimental model of lupus nephritis.Methods. MyD88 is a critical adaptor that is involved in signaling pathways through all of the Toll-like receptors (TLRs) except TLR-3. We therefore generated MyD88-knockout (MyD88-KO) MRL/lpr mice and examined them for histopathologic changes in the kidneys, cumulative survival rates, extent of lymphadenopathy and splenomegaly, serum chemistry, and immunologic parameters. In addition, to define the role of the MyD88-independent pathway in autoimmune nephritis, we injected MyD88-KO MRL/Ipr mice intraperitoneally with either poly(I-C) (50 or 100 jig per mouse) or phosphate buffered saline and examined them for survival as well as for histopathologic, serologic, and immunologic parameters.Results. In comparison with wild-type mice, MyD88-KO MRL/lpr mice exhibited a prolonged lifespan, with no apparent development of autoimmune nephritis. Their kidneys showed no glomerular cell proliferation or crescent formation, along with a drastic decrease in the mesangial matrix. Lymphadenopathy and splenomegaly were less pronounced. Serum titers of anti-double- stranded DNA (anti-dsDNA) and production of cytokines, including interferon-alpha (IFN alpha), interleukin-12 (IL-12), IL-6, and IFNy, in splenocytes were significantly reduced in MyD88-KO MRL/Ipr mice. Interestingly, MyD88-KO MRL/Ipr mice that had been treated with the MyD88-independent TLR-3 ligand poly(I-C) showed an almost complete reversion to the features of wild-type mice, demonstrating crescentic glomerulonephritis, with significant elevation of serum anti-dsDNA titers and increased cytokine production in splenocytes.Conclusion. The findings indicate that both MyD88-dependent and MyD88-independent innate signals play a crucial role in the development of autoimmune nephritis in MRL/Ipr mice.