Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals
Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals
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DOI：
10.1523/jneurosci.4290-06.2007
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发表时间：
2007-11-21
影响因子：
5.3
通讯作者：
Vartanian, Timothy
中科院分区：
文献类型：
--
作者：
Cameron, Jill S.;Alexopoulou, Lena;Vartanian, Timothy
Toll是一种细胞表面受体，在无脊椎动物的发育模式和成年果蝇的先天免疫中具有很好的描述作用。哺乳动物Toll样受体代表Toll直系同源家族，通过识别病原体或受损组织特有的分子基序在先天免疫中发挥作用。Toll样受体3（TLR3）是模式识别受体家族中的一员，它识别病毒双链RNA和宿主mRNA。我们研究了TLRs在神经系统中的表达和功能，发现TLR3在小鼠中枢和外周神经系统中表达，并集中在神经元的生长锥中。通过合成配体聚肌苷：聚胞苷酸（poly I：C）或通过mRNA激活TLR 3迅速引起生长锥塌陷并不可逆地抑制不依赖于核因子κ B的神经突延伸。缺乏功能性TLR3的小鼠对poly I：C的神经退行性作用具有抗性。新生小鼠注射聚I：C被发现有较少的轴突退出背根神经节，并显示相关的感觉运动缺陷。在缺乏功能性TLR3的小鼠中未观察到poly I：C的作用。总之，这些发现提供了证据，先天免疫模式识别受体的功能自主神经元调节轴突生长，并提出了一种新的假设，这类受体可能有助于损伤和有限的中枢神经系统再生。
Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine: polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor kappa B. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.