Respiratory, Inflammation and Autoimmunity Research Department, Gaithersburg, MD 20878, USA.
Department Immunology, St. Jude Children's Research Institute, Memphis, TN 38105, USA.
Immunity. 2012 Dec 14;37(6):986-997. doi: 10.1016/j.immuni.2012.09.014. Epub 2012 Dec 6.
Toll-like receptor-9 (TLR9) is largely responsible for discriminating self from pathogenic DNA. However, association of host DNA with autoantibodies activates TLR9, inducing the pathogenic secretion of type I interferons (IFNs) from plasmacytoid dendritic cells (pDCs). Here, we found that in response to DNA-containing immune complexes (DNA-IC), but not to soluble ligands, IFN-α production depended upon the convergence of the phagocytic and autophagic pathways, a process called microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP). LAP was required for TLR9 trafficking into a specialized interferon signaling compartment by a mechanism that involved autophagy-related proteins, but not the conventional autophagic preinitiation complex, or adaptor protein-3 (AP-3). Our findings unveil a new role for nonconventional autophagy in inflammation and provide one mechanism by which anti-DNA autoantibodies, such as those found in several autoimmune disorders, bypass the controls that normally restrict the apportionment of pathogenic DNA and TLR9 to the interferon signaling compartment.
Toll 样受体 9（TLR9）在很大程度上负责区分自身与致病性 DNA。然而，宿主 DNA 与自身抗体的结合会激活 TLR9，诱导浆细胞样树突状细胞（pDC）产生 I 型干扰素（IFN）。在这里，我们发现，针对含 DNA 的免疫复合物（DNA-IC），而非可溶性配体，IFN-α 的产生依赖于吞噬作用和自噬途径的收敛，这一过程称为微管相关蛋白 1A/1B-轻链 3（LC3）相关吞噬作用（LAP）。LAP 通过一种涉及自噬相关蛋白的机制，而不是常规的自噬起始复合物或衔接蛋白-3（AP-3），将 TLR9 转运到一个专门的干扰素信号隔室。我们的研究结果揭示了非典型自噬在炎症中的新作用，并提供了一种机制，即自身抗体（如几种自身免疫性疾病中发现的自身抗体）如何绕过通常限制致病性 DNA 和 TLR9 分配到干扰素信号隔室的控制。
