Exposure of female NZBWF1 mice to imiquimod-induced lupus nephritis at an early age via a unique mechanism that differed from spontaneous onset
Exposure of female NZBWF1 mice to imiquimod-induced lupus nephritis at an early age via a unique mechanism that differed from spontaneous onset
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雌性 NZBWF1 小鼠在幼年时通过不同于自发发病的独特机制暴露于咪喹莫特诱导的狼疮肾炎
DOI：
10.1093/cei/uxac012
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发表时间：
2022
影响因子：
4.6
通讯作者：
Sekigawa Iwao
中科院分区：
文献类型：
--
作者：
Hayakawa Kunihiro;Fujishiro Maki;Yoshida Yuko;Kataoka Yuko;Sakuma Shota;Nishi Takuya;Ikeda Keigo;Morimoto Shinji;Takamori Kenji;Sekigawa Iwao
系统性红斑狼疮（SLE）是一种具有代表性的慢性炎症性自身免疫性疾病。SLE的发病机制涉及各种遗传因素与个体对环境因素的易感性之间极其复杂的多因素相互作用。一些研究报道toll样受体（TLR） 7的突变和激活与自身免疫的发病有关，包括SLE。因此，我们研究了sled易感小鼠对持续环境因素的反应，特别是TLR7激动剂暴露，以及它们的表型变化。雌性和雄性NZBWF1 （BWF1）小鼠从20周龄开始用TLR7激动剂咪喹莫特（IMQ）治疗，每周3次，持续12周。暴露于imq的雌性BWF1小鼠狼疮性肾炎加重。然而，暴露于imq的雌性BWF1小鼠自身抗体的产生并未增强。imq处理小鼠肾脏中Th1细胞因子表达上调。在imq暴露的BWF1小鼠中，中和IFN-γ抑制早期狼疮肾炎。此外，在雄性BWF1小鼠中，IMQ暴露引起狼疮性肾炎轻微加重。这些结果表明，TLR7激动剂暴露诱导狼疮肾炎加重与急性TLR7信号诱导的肾炎症中IFN-γ的表达有关，并且与SLE易感性相关的遗传因素的参与也是必不可少的。因此，暴露于环境因素激活TLR7信号可能会破坏维持SLE缓解的因素平衡。我们假设TLR7信号和IFN-γ信号的抑制对预防狼疮性肾炎的发作和发作以及维持缓解有效。
Systemic lupus erythematosus (SLE) is a chronic inflammatory and representative autoimmune disease. Extremely complicated and multifactorial interactions between various genetic factors and individual susceptibility to environmental factors are involved in the pathogenesis of SLE. Several studies have reported that mutation and activation of toll-like receptor (TLR) 7 are involved in the onset of autoimmunity, including SLE. Thus, we investigated the response of SLE-prone mice to continuous environmental factors, particularly TLR7 agonist exposure, and changes in their phenotypes. Female and male NZBWF1 (BWF1) mice were treated from 20 weeks of age with a TLR7 agonist, imiquimod (IMQ), 3 times weekly for up to 12 weeks. IMQ-exposed female BWF1 mice showed worsened lupus nephritis. However, autoantibody production was not enhanced in IMQ-exposed female BWF1 mice. The Th1 cytokine expression was upregulated in the kidney of IMQ-treated mice. In IMQ-exposed BWF1 mice, neutralization of IFN-γ suppressed early-phase lupus nephritis. Additionally, in male BWF1 mice IMQ exposure induced minor aggravation of lupus nephritis. These results suggest that the induction of aggravated lupus nephritis by TLR7 agonist exposure was related to the expression of IFN-γ via acute TLR7 signal-induced renal inflammation, and that the involvement of genetic factors associated with a predisposition to SLE is also essential. Thus, the activation of TLR7 signaling by exposure to environmental factors may upset the balance of factors that maintain SLE remission. We hypothesize that the inhibition of TLR7 signaling and IFN-γ signaling is effective for preventing the onset and flare and maintaining remission of lupus nephritis.