TLR7/TLR8 activation and susceptibility genes synergize to breach gut barrier in a mouse model of lupus.
TLR7/TLR8 activation and susceptibility genes synergize to breach gut barrier in a mouse model of lupus.
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TLR7/TLR8 激活和易感基因协同作用，突破狼疮小鼠模型的肠道屏障。
DOI：
10.3389/fimmu.2023.1187145
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
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作者：
越来越多的证据表明，肠道通透性增加，或肠道渗漏，以及由此产生的致病菌或其代谢产物的易位有助于系统性红斑狼疮的发病机制。然而，诱导肠漏的机制仍不清楚。在这项研究中，我们研究了B6.Sle1.Sle2.Sle3三重同源（TC）小鼠，一个自发的狼疮小鼠模型，没有肠漏的TLR7/8激动剂的治疗效果。用R848处理狼疮易感小鼠（TC）、缺乏B和T细胞的TC.Rag1-/-小鼠和同源B6健康对照。通过测量口服管饲后血清中的FITC-葡聚糖来评估肠道屏障完整性。通过免疫荧光法测量回肠中紧密连接蛋白-1和PECAM 1的表达以及CD 45+免疫细胞、B220 + B细胞、CD 3 + T细胞和CD 11 B+骨髓细胞的程度。通过免疫荧光测量回肠和结肠中的NKp46+细胞。还通过流式细胞术分析回肠中的免疫细胞。R848降低TC小鼠的肠道屏障完整性，但在同类对照B6小鼠中不降低。回肠的免疫荧光染色显示，与未处理的对照小鼠相比，在R848处理的TC中，紧密连接蛋白Claudin-1、内皮细胞紧密连接PECAM 1的表达减少，以及免疫细胞（包括B细胞和CD 11 B+细胞）的浸润增加。然而，在维持肠道屏障完整性中起关键作用的NKp46+细胞在治疗的TC小鼠中具有较低的频率。流式细胞术显示，在R848处理的TC小鼠固有层中，浆细胞、树突状细胞和巨噬细胞的频率增加，而NK细胞的频率降低。此外，我们发现R848处理不会诱导缺乏成熟T和B细胞的TC. Rag1-/-小鼠的肠漏。这些结果表明，TLR7/8激活诱导狼疮易感小鼠的肠道渗漏，这是由适应性免疫应答介导的。然而，TLR7/8活化不足以破坏非自身免疫小鼠中的肠道屏障完整性。
Mounting evidence suggests that increased gut permeability, or leaky gut, and the resulting translocation of pathobionts or their metabolites contributes to the pathogenesis of Systemic Lupus Erythematosus. However, the mechanisms underlying the induction of gut leakage remain unclear. In this study, we examined the effect of a treatment with a TLR7/8 agonist in the B6.Sle1.Sle2.Sle3 triple congenic (TC) mouse, a spontaneous mouse model of lupus without gut leakage. Lupus-prone mice (TC), TC.Rag1-/- mice that lack B and T cells, and congenic B6 healthy controls were treated with R848. Gut barrier integrity was assessed by measuring FITC-dextran in the serum following oral gavage. Claudin-1 and PECAM1 expression as well as the extent of CD45+ immune cells, B220+ B cells, CD3+ T cells and CD11b+ myeloid cells were measured in the ileum by immunofluorescence. NKp46+ cells were measured in the ileum and colon by immunofluorescence. Immune cells in the ileum were also analyzed by flow cytometry. R848 decreased gut barrier integrity in TC but not in congenic control B6 mice. Immunofluorescence staining of the ileum showed a reduced expression of the tight junction protein Claudin-1, endothelial cell tight junction PECAM1, as well as an increased infiltration of immune cells, including B cells and CD11b+ cells, in R848-treated TC as compared to untreated control mice. However, NKp46+ cells which play critical role in maintaining gut barrier integrity, had a lower frequency in treated TC mice. Flow cytometry showed an increased frequency of plasma cells, dendritic cells and macrophages along with a decreased frequency of NK cells in R848 treated TC mice lamina propria. In addition, we showed that the R848 treatment did not induce gut leakage in TC.Rag1-/- mice that lack mature T and B cells. These results demonstrate that TLR7/8 activation induces a leaky gut in lupus-prone mice, which is mediated by adaptive immune responses. TLR7/8 activation is however not sufficient to breach gut barrier integrity in non-autoimmune mice.
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DOI：
10.1097/shk.0000000000000900
发表时间：
2017-12
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Hammer AM;Morris NL;Cannon AR;Khan OM;Gagnon RC;Movtchan NV;van Langeveld I;Li X;Gao B;Choudhry MA
通讯作者：
Choudhry MA
影响因子：
7.3
作者：
Ma, Longhuan;Morel, Laurence
通讯作者：
Morel, Laurence
影响因子：
30.5
作者：
通讯作者：
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影响因子：
32.4
作者：
Lee JS;Tato CM;Joyce-Shaikh B;Gulen MF;Cayatte C;Chen Y;Blumenschein WM;Judo M;Ayanoglu G;McClanahan TK;Li X;Cua DJ
通讯作者：
Cua DJ
TLR7 功能获得性遗传变异导致人类狼疮
影响因子：
64.8
作者：
通讯作者：
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