Endotoxin Tolerance Induced by Different TLR Ligands
Endotoxin Tolerance Induced by Different TLR Ligands
复制标题
不同TLR配体诱导的内毒素耐受
DOI：
10.1101/250415
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Butcher S
中科院分区：
文献类型：
--
作者：
Butcher S
内毒素耐受性是巨噬细胞的一种长期公认的特性，其导致对重复或慢性暴露于Toll样受体（TLR）配体的反应改变。耐受性的生理作用是限制对宿主组织的潜在损伤，否则可能由促炎细胞因子的长期产生引起。内毒素耐受性由迄今为止测试的所有TLR诱导，然而，由TLR 4配体脂多糖（LPS）诱导的耐受性是迄今为止研究得最好的。LPS耐受性涉及从促炎反应向以抗炎和促消退因子的表达为特征的反应的整体转录转变。虽然在很大程度上是可逆的，但LPS耐受性导致混合巨噬细胞活化状态，其本质上是促炎性的，但具有独特的调节抗炎特征。值得注意的是，由不同TLR配体诱导的耐受性的比较转录组学分析先前尚未报道。在这里，我们描述的转录谱的小鼠巨噬细胞与TLR2，TLR3，TLR4和TLR9的配体耐受。虽然我们在用每种配体耐受的巨噬细胞中鉴定了TLR特异性转录谱，但由TLR4诱导的耐受是最全面的状态，使得被任何测试的TLR耐受的每种基因也被发现被TLR4耐受。促炎性细胞因子并不是在所有耐受细胞中普遍被抑制，但不同的细胞因子表达模式区分TLR特异性耐受。基因调控区的分析揭示了与TLR耐受性的不同状态相关的特定DNA序列基序，涉及先前确定的以及新的巨噬细胞耐受性的转录调节因子。这些数据为将来开发TLR特异性耐受状态以实现先天免疫应答的治疗性重编程提供了基础。
Endotoxin tolerance is a long-recognised property of macrophages that leads to an altered response to repeated or chronic exposure to Toll-like receptor (TLR) ligands. The physiological role of tolerance is to limit the potential damage to host tissue that may otherwise result from prolonged production of pro-inflammatory cytokines. Endotoxin tolerance is induced by all TLRs tested to date, however, tolerance induced by the TLR4 ligand lipopolysaccharide (LPS) is by far the best studied. LPS tolerance involves a global transcriptional shift from a pro-inflammatory response toward one characterised by the expression of anti-inflammatory and pro-resolution factors. Although largely reversible, LPS-tolerance leads to a hybrid macrophage activation state that is pro-inflammatory in nature but possesses distinct regulatory anti-inflammatory features. Remarkably, a comparative transcriptomic analysis of tolerance induced by different TLR ligands has not previously been reported. Here we describe the transcriptomic profiles of mouse macrophages tolerised with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerised with each ligand, tolerance induced by TLR4 was the most comprehensive state, such that each gene tolerised by any of the TLRs tested was also found to be tolerised by TLR4. Pro-inflammatory cytokines are not universally supressed in all tolerant cells but distinct patterns of cytokine expression distinguished TLR-specific tolerance. Analysis of gene regulatory regions revealed specific DNA sequence motifs associated with distinct states of TLR tolerance, implicating previously identified as well as novel transcriptional regulators of tolerance in macrophages. These data provide a basis for the future exploitation of TLR-specific tolerant states to achieve therapeutic re-programming of the innate immune response.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
CpG DNA 诱导体内 IL-12 持续表达并抵抗单核细胞增生李斯特氏菌的攻击。
DOI：
--
发表时间：
1998
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Krieg,AM;Love-Homan,L;Yi,AK;Harty,JT
通讯作者：
Harty,JT