Low-Dose LPS Induces Tolerogenic Treg Skewing in Asthma.
Low-Dose LPS Induces Tolerogenic Treg Skewing in Asthma.
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低剂量 LPS 诱导哮喘耐受性 Treg 偏差
DOI：
10.3389/fimmu.2020.02150
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发表时间：
2020
影响因子：
7.3
通讯作者：
Fu Z
中科院分区：
文献类型：
--
作者：
Ding F;Liu B;Niu C;Wang T;Wang Y;Geng G;Tian D;Dai J;Fu Z
内毒素耐受在哮喘中的作用机制仍不清楚。由于内毒素脂多糖（LPS）影响调节性T细胞（Treg）抑制性糖皮质激素诱导的肿瘤坏死因子受体配体（GITRL）在抗原呈递树突状细胞（DC）上的表达，我们假设LPS诱导的DC GITRL表达的变化可能影响Treg介导的T辅助（Th）细胞抑制和内毒素耐受的诱导。在这里，我们提出了一种新的机制，低剂量LPS吸入新生小鼠诱导内毒素耐受，从而提供保护，从以后的哮喘发展。在卵清蛋白（OVA）诱导的哮喘之前，将三日龄野生型和Toll样受体4（TLR 4）缺陷的新生小鼠鼻内暴露于低剂量LPS（1 μg）连续10天，以更好地理解低剂量LPS预暴露的致耐受性机制。使用在OVA刺激之前有或没有低剂量LPS预暴露的原代CD 11 c + DC和CD 4 + T细胞的体外共培养研究来验证体内发现。低剂量LPS预暴露通过促进Th 2和Th 17细胞凋亡上调Treg反应，下调致病性Th 2和Th 17反应。低剂量LPS预暴露下调DC GITRL表达和T细胞GITR表达。人工DC GITRL表达消除了低剂量LPS预暴露的致耐受性Treg偏移效应。低剂量LPS预暴露抑制TRIF/IRF 3/IFNβ信号传导，并以TLR 4依赖的方式上调致耐受性TRIF/IRF 3/IFNβ负调控因子的表达。这种致耐受性DC GITRL下调归因于TRIF/IRF 3/IFNβ信号传导抑制。低剂量LPS预暴露在新生哮喘小鼠中产生致耐受性Treg偏斜，这一现象归因于TLR 4依赖性TRIF/IRF 3/IFNβ介导的DC GITRL下调。
The mechanism(s) underlying endotoxin tolerance in asthma remain elusive. As the endotoxin lipopolysaccharide (LPS) affects the expression of the regulatory T-cell (Treg)-suppressive glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) on antigen-presenting dendritic cells (DCs), we hypothesized that LPS-induced changes in DC GITRL expression may impact Treg-mediated T-helper (Th) cell suppression and the induction of endotoxin tolerance. Here, we propose a novel mechanism by which low-dose LPS inhalation in neonatal mice induces endotoxin tolerance, thereby offering protection from later asthma development. Three-day old wild-type and Toll-like receptor 4 (TLR4)-deficient neonatal mice were exposed to low-dose LPS (1 μg) intranasally for 10 consecutive days prior to ovalbumin (OVA)-induced asthma to better understand the tolerogenic mechanism(s) of low-dose LPS pre-exposure. In vivo findings were validated using in vitro co-culturing studies of primary CD11c+ DCs and CD4+ T-cells with or without low-dose LPS pre-exposure before OVA stimulation. Low-dose LPS pre-exposure upregulated the Treg response and downregulated pathogenic Th2 and Th17 responses through promoting apoptosis of Th2 and Th17 cells. Low-dose LPS pre-exposure downregulated DC GITRL expression and T-cell GITR expression. Artificial DC GITRL expression abrogated the tolerogenic Treg-skewing effect of low-dose LPS pre-exposure. Low-dose LPS pre-exposure inhibited TRIF/IRF3/IFNβ signaling and upregulated expression of tolerogenic TRIF/IRF3/IFNβ negative regulators in a TLR4-dependent manner. This tolerogenic DC GITRL downregulation was attributable to TRIF/IRF3/IFNβ signaling inhibition. Low-dose LPS pre-exposure produces tolerogenic Treg skewing in neonatal asthmatic mice, a phenomenon attributable to TLR4-dependent TRIF/IRF3/IFNβ-mediated DC GITRL downregulation.
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影响因子：
6.1
作者：
Maazi, H.;Shirinbak, S.;van Oosterhout, A. J. M.
通讯作者：
van Oosterhout, A. J. M.
影响因子：
3.6
作者：
Xu, Hongmei;An, Huazhang;Cao, Xuetao
通讯作者：
Cao, Xuetao
GITR信号传导通过在哮喘的小鼠模型中增强Th2细胞活性来增强气道高反应性。
影响因子：
5.8
作者：
Motta AC;Vissers JL;Gras R;Van Esch BC;Van Oosterhout AJ;Nawijn MC
通讯作者：
Nawijn MC
影响因子：
8.3
作者：
Ferkol, Thomas;Schraufnagel, Dean
通讯作者：
Schraufnagel, Dean
影响因子：
14.2
作者：
Barlow, Jillian L.;Peel, Samantha;McKenzie, Andrew N. J.
通讯作者：
McKenzie, Andrew N. J.