Glycolipid iGb3 feedback amplifies innate immune responses via CD1d reverse signaling
Glycolipid iGb3 feedback amplifies innate immune responses via CD1d reverse signaling
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糖脂 iGb3 反馈通过 CD1d 反向信号传导放大先天免疫反应。
DOI：
10.1038/s41422-018-0122-7
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发表时间：
2019-01-01
期刊：
影响因子：
44.1
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
--
作者：
Liu, Xingguang;Zhang, Peng;Cao, Xuetao
细胞脂质代谢和先天免疫反应之间的相互作用仍然不清楚。除了将脂质抗原呈递给自然杀伤T细胞（NKT细胞）外，分化簇1D糖蛋白（CD 1d）可能介导抗原呈递细胞（APC）中的反向信号传导。在这里，我们发现CD 1d缺陷减弱了巨噬细胞和树突状细胞中Toll样受体（TLR）触发的先天性炎症反应，保护小鼠免受内毒素休克。巨噬细胞TLR活化引起鞘糖脂（GSL）代谢变化，其中糖脂异三己糖神经酰胺（iGb 3）迅速产生。内源性产生的iGb 3结合内体区室中的CD 1d，然后与最初激活的TLR信号协同诱导CD 1d胞内结构域的Tyr 332磷酸化。这导致富含脯氨酸的酪氨酸激酶2（Pyk 2）的募集和活化。Pyk 2与I κ B激酶β（IKK β）和TANK结合激酶1（TBK 1）相互作用，并增强IKK β的Tyr 188/199和TBK 1的Tyr 179的酪氨酸磷酸化，从而增强它们的活化以促进TLR信号传导的完全活化。因此，由内源性iGb 3触发的细胞内CD 1d反向信号传导放大了APC中的先天性炎症反应。我们的研究结果确定了一个非典型的功能CD 1d反向信号激活的脂质代谢产物在先天性免疫反应。
The cross-talk between cellular lipid metabolism and the innate immune responses remains obscure. In addition to presenting lipid antigens to Natural Killer T-cells (NKT cells), the Cluster of Differentiation 1D Glycoprotein (CD1d) might mediate reverse signaling in antigen-presenting cells (APCs). Here we found CD1d deficiency attenuated Toll-like receptor (TLR)-triggered inflammatory innate responses in macrophages and dendritic cells, protecting mice from endotoxin shock. TLR activation in macrophages induced metabolic changes of glycosphingolipids (GSLs), among which glycolipid isoglobotrihexosylceramide (iGb3) was rapidly produced. The endogenously generated iGb3 bound CD1d in endosomal compartments and then synergized with the initially activated TLR signal to induce Tyr332 phosphorylation of CD1d intracellular domain. This led to the recruitment and activation of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 interacted with I kappa B kinase beta (IKK beta) and TANK-binding kinase 1 (TBK1), and enhanced tyrosine phosphorylation of Tyr188/199 of IKK beta and Tyr179 of TBK1 and thus, their activation to promote full activation of TLR signaling. Thus, intracellular CD1d reverse signaling, triggered by endogenous iGb3, amplifies inflammatory innate responses in APCs. Our findings identify a non-canonical function of CD1d reverse signaling activated by lipid metabolite in the innate immune response.