Lupus Autoimmunity and Metabolic Parameters Are Exacerbated Upon High Fat Diet-Induced Obesity Due to TLR7 Signaling
Lupus Autoimmunity and Metabolic Parameters Are Exacerbated Upon High Fat Diet-Induced Obesity Due to TLR7 Signaling
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DOI：
10.3389/fimmu.2019.02015
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发表时间：
2019-09-04
影响因子：
7.3
通讯作者：
Alexopoulou, Lena
中科院分区：
文献类型：
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作者：
Kazazian, Noel Hanna;Wang, Yawen;Alexopoulou, Lena
系统性红斑狼疮（SLE）患者代谢综合征患病率增加，但其潜在机制尚不清楚。toll样受体7 （TLR7）检测单链rna，在抗微生物宿主防御中起关键作用，也有助于小鼠和人类SLE的发生和进展。在这里，我们报道了TLR7信号在高脂肪饮食（HFD）诱导的代谢综合征和狼疮自身免疫恶化中的意义，tlr8缺陷（TLR8ko）小鼠由于树突状细胞（dc）的TLR7信号增加而发生自发性狼疮样疾病。hfd喂养的TLR8ko小鼠SLE发病机制的恶化表现为整体免疫激活、抗dna自身抗体产生和IgG/IgM肾小球沉积增加，并伴有肾脏组织病理学的增加。此外，在HFD后，TLR8ko小鼠出现代谢异常，包括肝脏炎症。相比之下，在HFD治疗下，TLR7/8ko小鼠没有发生SLE， TLR7/8ko和TLR7/8ko小鼠完全免受代谢异常的影响，包括体重增加、胰岛素抵抗和肝脏炎症。有趣的是，HFD导致WT小鼠中TLR7表达增加，这与dc产生的TNF增加相结合，并且这种表型在TLR8ko小鼠中更为深刻。我们的研究揭示了TLR7信号在SLE和代谢异常互连中的意义，表明TLR7可能是一种针对SLE和代谢性疾病的量身定制治疗的新方法。
Systemic lupus erythematosus (SLE) patients have increased prevalence of metabolic syndrome but the underlying mechanisms are unknown. Toll-like receptor 7 (TLR7) that detects single stranded-RNA plays a key role in antimicrobial host defense and also contributes to the initiation and progression of SLE both in mice and humans. Here, we report the implication of TLR7 signaling in high fat diet (HFD)-induced metabolic syndrome and exacerbation of lupus autoimmunity in TLR8-deficient (TLR8ko) mice, which develop spontaneous lupus-like disease due to increased TLR7 signaling by dendritic cells (DCs). The aggravated SLE pathogenesis in HFD-fed TLR8ko mice was characterized by increased overall immune activation, anti-DNA autoantibody production, and IgG/IgM glomerular deposition that were coupled with increased kidney histopathology. Moreover, upon HFD TLR8ko mice developed metabolic abnormalities, including liver inflammation. In contrast, upon HFD TLR7/8ko mice did not develop SLE and both TLR7ko and TLR7/8ko mice were fully protected from metabolic abnormalities, including body weight gain, insulin resistance, and liver inflammation. Interestingly, HFD led to an increase of TLR7 expression in WT mice, that was coupled with increased TNF production by DCs, and this phenotype was more profound in TLR8ko mice. Our study uncovers the implication of TLR7 signaling in the interconnection of SLE and metabolic abnormalities, indicating that TLR7 might be a novel approach as a tailored therapy in SLE and metabolic diseases.