TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice
TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice
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DOI：
10.1073/pnas.1314121111
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发表时间：
2014-01-28
影响因子：
11.1
通讯作者：
Alexopoulou, Lena
中科院分区：
文献类型：
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作者：
Desnues, Benoit;Macedo, Amanda Beatriz;Alexopoulou, Lena
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，临床表现多样，其特征在于存在针对核成分的自身抗体。Toll样受体（TLR）7、TLR 8和TLR 9是敏感微生物或内源性核酸，并与SLE的发展有关。在小鼠中，TLR 7缺陷改善SLE，但TLR 8或TLR 9缺陷由于TLR 7反应增加而使疾病恶化。因此，TLR 8和TLR 9都控制TLR 7的功能，但TLR 8和TLR 9在控制TLR 7介导的狼疮中是否在相同或不同的细胞类型中平行或串联起作用仍是未知的。在此，我们发现，与单个TLR 8（-/-）或TLR 9（-/-）小鼠相比，C57 BL/6背景下的双TLR 8/9缺陷（TLR 8/9（-/-））小鼠显示SLE特征性异常增加，包括脾肿大、自身抗体产生、边缘区和B1 B细胞的频率以及肾脏病理学。在细胞水平上，TLR 8（-/-）和TLR 8/9（-/-）树突状细胞对TLR 7配体R848反应强烈，而TLR 9（-/-）细胞反应正常。此外，TLR 9（-/-）和TLR 8/9（-/-）小鼠的B细胞对R848有高反应性，而TLR 8（-/-）B细胞对R848无反应性。这些结果表明，TLR 8和TLR 9对控制TLR 7功能和TLR 7介导的狼疮具有累加效应;然而，它们作用于不同的细胞类型。TLR 8控制树突细胞上的TLR 7功能，而TLR 9抑制B细胞上的TLR 7应答。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sensemicrobial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9(-/-)) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8(-/-) or TLR9(-/-) mice. On the cellular level, TLR8(-/-) and TLR8/9(-/-) dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9(-/-) cells responded normally. Moreover, B cells from TLR9(-/-) and TLR8/9(-/-) mice were hyperesponsive to R848, but TLR8(-/-) B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells.