Toll-Like Receptors Drive Specific Patterns of Tolerance and Training on Restimulation of Macrophages.
Toll-Like Receptors Drive Specific Patterns of Tolerance and Training on Restimulation of Macrophages.
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DOI：
10.3389/fimmu.2018.00933
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发表时间：
2018
影响因子：
7.3
通讯作者：
Carmody RJ
中科院分区：
文献类型：
--
作者：
Butcher SK;O'Carroll CE;Wells CA;Carmody RJ
耐受性是巨噬细胞长期公认的特性，其导致对重复或慢性暴露于内毒素的反应改变。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。耐受性由迄今为止测试的所有toll样受体（TLR）配体诱导，然而，由TLR4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。虽然我们鉴定了用每种配体耐受的巨噬细胞中的TLR特异性转录谱，但由TLR4诱导的耐受代表了原型模式，使得还发现由任何测试的TLR耐受的每种基因也被TLR4耐受。促炎细胞因子在所有耐受细胞中并不普遍受到抑制，但细胞因子表达的不同模式区分了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。
Tolerance is a long-recognized property of macrophages that leads to an altered response to repeated or chronic exposure to endotoxin. 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. Tolerance is induced by all toll-like receptor (TLR) ligands 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 characterized 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 tolerized with ligands for TLR2, TLR3, TLR4 and TLR 9. While we identified TLR-specific transcriptional profiles in macrophages tolerized with each ligand, tolerance induced by TLR4 represented an archetype pattern, such that each gene tolerized by any of the TLRs tested was also found to be tolerized by TLR4. Pro-inflammatory cytokines are not universally suppressed 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.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
4.4
作者：
O'Carroll, Christine;Fagan, Ailis;Carmody, Ruaidhri J.
通讯作者：
Carmody, Ruaidhri J.
影响因子：
3.7
作者：
Julian MW;Strange HR;Ballinger MN;Hotchkiss RS;Papenfuss TL;Crouser ED
通讯作者：
Crouser ED
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
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