MicroRNA21 Meets Neuronal TLR8: Non-canonical Functions of MicroRNA in Neuropathic Pain
MicroRNA21 Meets Neuronal TLR8: Non-canonical Functions of MicroRNA in Neuropathic Pain
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MicroRNA21 与神经元 TLR8 的结合：MicroRNA 在神经病理性疼痛中的非典型功能
DOI：
10.1007/s12264-019-00366-9
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发表时间：
2019-03
影响因子：
5.6
通讯作者：
Tong Liu
中科院分区：
文献类型：
--
作者：
Zhi-Hong Wang;Tong Liu
Toll样受体（TLR）是免疫系统中众所周知的模式识别受体，用于识别病原体相关和损伤相关的分子模式[1]。TLR在先天性和适应性免疫应答中起重要作用。迄今为止，已在人类中鉴定了10种功能性TLR（TLR 1-TLR 10），在小鼠中鉴定了12种功能性TLR（TLR 1-TLR 9和TLR 11-TLR 13）[1]。TLR是进化上保守的I型跨膜蛋白，包含以介导配体识别的富含亮氨酸的重复序列为特征的胞外域、跨膜区和激活下游信号传导途径的胞质Toll-白细胞介素（IL）-1受体结构域[1]。大多数类型的TLR在它们之间形成同源二聚体，但某些TLR也可以形成异源二聚体，例如TLR 1/TLR 2和TLR 2/TLR 6。衔接蛋白MyD 88是大多数TLR的下游信号传导所需的，但不是TLR 3信号传导所需的。接头蛋白TRIF（含TIR结构域的接头诱导干扰素B）被TLR 3和TLR 4使用，最终激活核因子κ B（NF j B）和干扰素调节因子3。在免疫系统中，TLR 1、TLR 2、TLR 4、TLR 5、TLR 6和TLR 10位于质膜中以识别细菌膜组分，而TLR 3、TLR 7、TLR 8和TLR 9主要位于细胞内核内体中以识别基于核酸的配体。免疫细胞对TLR的典型参与启动细胞内信号传导途径，导致炎性细胞因子和趋化因子的合成和释放[1]。越来越多的证据表明，TLR也在中枢和外周神经系统、小胶质细胞、星形胶质细胞、内皮细胞和神经元中表达。神经系统中的TLR在中风、神经退行性疾病、多发性硬化和慢性疼痛的发病机制中起关键作用[2，3]。因此，靶向TLR可能是治疗许多神经系统疾病的有前途的策略。TLR位于神经免疫界面，并在神经元和非神经元细胞中被激活;它们通过直接激活初级感觉神经元和通过非神经元细胞间接产生促炎介质来调节伤害感受和伤害感受信号处理[3，4]。TLR 2、TLR 3、TLR 4、TLR 5、TLR 7和TLR 9由背根神经节（DRG）中的初级感觉神经元表达，并在疼痛和瘙痒的产生中发挥重要作用[3，5]。TLR 2和TLR 4介导脊髓中的胶质细胞活化（星形胶质细胞和小胶质细胞），并促进慢性疼痛和慢性瘙痒的发展[4，6]。有趣的是，神经元TLR具有不同的亚细胞分布。例如，神经元TLR 7位于DRG神经元的质膜上，与离子通道瞬时受体电位A1偶联，调节神经元兴奋性和疼痛[5]。然而，神经元TLRs的亚细胞分布、下游信号传导和内源性配体及其在慢性疼痛中的作用仍不清楚。在最近发表在《实验医学杂志》（2018年12月）上的一项研究中，Zhang及其同事报告了一个惊人的发现，即DRG初级感觉神经元中的TLR 8及其内源性配体miR-21有助于小鼠的神经性疼痛[7]。由于Tlr 7和Tlr 8基因高度同源，
Toll-like receptors (TLRs) are well-known as patternrecognition receptors in the immune system for recognizing pathogen-associated and damage-associated molecular patterns [1]. TLRs play an essential role in the innate and adaptive immune responses. To date, 10 functional TLRs have been identified in humans (TLR1–TLR10) and 12 in mice (TLR1–TLR9 and TLR11–TLR13)[1]. TLRs are evolutionarily conserved type I transmembrane proteins and comprise an ectodomain characterized by leucine-rich repeats mediating the recognition of ligands, a transmembrane region, and cytosolic Toll-interleukin (IL)-1 receptor domains that activate the downstream signaling pathways [1]. Most types of TLRs form homodimers between themselves, but certain TLRs can also form heterodimers, such as TLR1/TLR2 and TLR2/TLR6. The adaptor protein MyD88 is required for the downstream signaling of most TLRs, but not for TLR3 signaling. The adaptor protein TRIF (TIR-domain-containing adapter-inducing interferonb) is used by TLR3 and TLR4, culminating in the activation of nuclear factor kappa B (NFjB) and interferon regulatory factor 3. In the immune system, TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located in the plasma membrane to recognize bacterial membrane components, whereas TLR3, TLR7, TLR8, and TLR9 are predominantly located within intracellular endosomes to recognize nucleic acid-based ligands. Typical engagement of TLRs by immune cells initiates intracellular signaling pathways, leading to the synthesis and release of inflammatory cytokines and chemokines [1]. Mounting evidence has demonstrated that TLRs are also expressed in the central and peripheral nervous systems, in microglia, astrocytes, endothelial cells, and neurons. TLRs in the nervous system play pivotal roles in the pathogenesis of stroke, neurodegenerative diseases, multiple sclerosis, and chronic pain [2, 3]. Thus, targeting TLRs may be a promising strategy for treating many neurological disorders. TLRs are positioned at the neuroimmune interface and are activated in neuronal and non-neuronal cells; they modulate nociceptive and pruriceptive signal processing by direct activation of primary sensory neurons and via the indirect production of pro-inflammatory mediators by nonneuronal cells [3, 4]. TLR2, TLR3, TLR4, TLR5, TLR7, and TLR9 are expressed by primary sensory neurons in the dorsal root ganglia (DRG) and play important roles in the generation of pain and itch [3, 5]. TLR2 and TLR4 mediate glial activation (astrocytes and microglia) in the spinal cord and contribute to the development of chronic pain and chronic itch [4, 6]. Interestingly, neuronal TLRs have distinct subcellular distributions. For example, neuronal TLR7 is located in the plasma membrane of DRG neurons, and couples with the ion channel transient receptor potential A1 to regulate neuronal excitability and pain [5]. However, the subcellular distribution, downstream signaling, and endogenous ligands of neuronal TLRs and their roles in chronic pain are still not well understood. In a recently published study in the Journal of Experimental Medicine (December, 2018), Zhang and colleagues reported the striking finding that TLR8 and its endogenous ligand miR-21 in primary sensory neurons of the DRG contribute to neuropathic pain in mice [7]. Given that the Tlr7 and Tlr8 genes are highly homologous and are both
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影响因子：
16.2
作者：
Han Q;Liu D;Convertino M;Wang Z;Jiang C;Kim YH;Luo X;Zhang X;Nackley A;Dokholyan NV;Ji RR
通讯作者：
Ji RR
影响因子：
5.6
作者：
Liu, Tong;Gao, Yong-Jing;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
影响因子：
16.2
作者：
Park CK;Xu ZZ;Berta T;Han Q;Chen G;Liu XJ;Ji RR
通讯作者：
Ji RR
Toll样受体8充当神经突生长的负调节剂和神经元凋亡的诱导剂。
DOI：
10.1083/jcb.200606016
发表时间：
2006-10-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ma Y;Li J;Chiu I;Wang Y;Sloane JA;Lü J;Kosaras B;Sidman RL;Volpe JJ;Vartanian T
通讯作者：
Vartanian T
影响因子：
25
作者：
Liu, Tong;Xu, Zhen-Zhong;Park, Chul-Kyu;Berta, Temugin;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong