Glycolipid iGb3 feedback amplifies innate immune responses via CD1d reverse signaling
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 1 D Glycoprotein (CD1d) might mediate reverse signaling in antigen-presenting cells (APCs).Here we found CD1d deficiency attenuated Toll-like receptor (TkR)-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 IKB kinase β3 (IKKβ) and TANK-binding kinase 1 (TBK1),and enhanced tyrosine phosphorylation of Tyr188/199 of IKKβ3 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.
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We thank Dr. H. Shen University of Pennsylvania for Listeria monocytogenes;X. Sun and M. Jin for technical assistance. This work was supported by the National Key Basic Research Program of China2015CB964403 to X.C.;the National Natural Science Foundation of China81788101 to X.C., 31570871 to X.L., 31770970 to X.L,81600182 to P.Z., 81571543 to Y.L.;CAMS Innovation Fund for Medical Sciences2016-12M-1-003 to X.C.;”Shuguang Program” of Shanghai Education Development Foundation and Shanghai Municipal Education Commission18SG33 to X.L.
2019-03-08（万方平台首次上网日期，不代表论文的发表时间）
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