Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics.
Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics.
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DOI：
10.3389/fphys.2017.00508
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发表时间：
2017
影响因子：
4
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Gao W;Xiong Y;Li Q;Yang H
Toll样受体（TLR）识别入侵的病原体和来自受损组织的内源性分子，触发保护性自卫机制。然而，过度的TLR活化通过持续的促炎细胞因子和趋化因子产生破坏免疫稳态，并因此导致许多炎性和自身免疫性疾病的发展，例如系统性红斑狼疮（SLE）、感染相关的脓毒症、动脉粥样硬化和哮喘。因此，靶向TLR信号的抑制剂/拮抗剂可能有益于治疗这些疾病。本文首先对TLRs在炎症性疾病中的病理生理作用作一简要综述。然后，我们重点审查目前的知识，在临床前和临床研究的各种TLR拮抗剂/抑制剂的预防和治疗炎症性疾病。这些化合物的范围从传统的小分子到治疗性生物制剂和纳米器件。特别是，纳米器件正在成为一类新的有效TLR抑制剂，因为它们在所需的生物分布、持续循环和优选的药效学和药代动力学特征方面具有独特的性质。更有趣的是，这些纳米器件的抑制活性可以通过精确的纳米功能化来调节，使它们成为下一代治疗剂或“纳米药物”。尽管已经在开发不同种类的新TLR抑制剂/拮抗剂方面做出了显著的努力，但是其中只有有限数量的TLR抑制剂/拮抗剂经历了临床试验，并且迄今为止没有一种TLR抑制剂/拮抗剂被批准用于临床用途。然而，这些发现和TLR抑制的持续研究突出了TLR信号传导的药理学调节，特别是对多个TLR通路的药理学调节，作为各种炎症和自身免疫性疾病的未来有前途的治疗策略。
The recognition of invading pathogens and endogenous molecules from damaged tissues by toll-like receptors (TLRs) triggers protective self-defense mechanisms. However, excessive TLR activation disrupts the immune homeostasis by sustained pro-inflammatory cytokines and chemokines production and consequently contributes to the development of many inflammatory and autoimmune diseases, such as systemic lupus erythematosus (SLE), infection-associated sepsis, atherosclerosis, and asthma. Therefore, inhibitors/antagonists targeting TLR signals may be beneficial to treat these disorders. In this article, we first briefly summarize the pathophysiological role of TLRs in the inflammatory diseases. We then focus on reviewing the current knowledge in both preclinical and clinical studies of various TLR antagonists/inhibitors for the prevention and treatment of inflammatory diseases. These compounds range from conventional small molecules to therapeutic biologics and nanodevices. In particular, nanodevices are emerging as a new class of potent TLR inhibitors for their unique properties in desired bio-distribution, sustained circulation, and preferred pharmacodynamic and pharmacokinetic profiles. More interestingly, the inhibitory activity of these nanodevices can be regulated through precise nano-functionalization, making them the next generation therapeutics or “nano-drugs.” Although, significant efforts have been made in developing different kinds of new TLR inhibitors/antagonists, only limited numbers of them have undergone clinical trials, and none have been approved for clinical uses to date. Nevertheless, these findings and continuous studies of TLR inhibition highlight the pharmacological regulation of TLR signaling, especially on multiple TLR pathways, as future promising therapeutic strategy for various inflammatory and autoimmune diseases.
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影响因子：
6.1
作者：
Bomfim GF;Echem C;Martins CB;Costa TJ;Sartoretto SM;Dos Santos RA;Oliveira MA;Akamine EH;Fortes ZB;Tostes RC;Webb RC;Carvalho MH
通讯作者：
Carvalho MH
影响因子：
3.1
作者：
Bergt, Stefan;Wagner, Nana-Maria;Roesner, Jan P.
通讯作者：
Roesner, Jan P.
DOI：
10.1590/s0074-02762013000500010
发表时间：
2013-08-01
期刊：
Memórias do Instituto Oswaldo Cruz
影响因子：
--
作者：
Borges, Marcos Carvalho;Castro, Luiza Antunes;Fonseca, Benedito Antonio Lopes da
通讯作者：
Fonseca, Benedito Antonio Lopes da
影响因子：
10.8
作者：
Babazada, Hasan;Yamashita, Fumiyoshi;Hashida, Mitsuru
通讯作者：
Hashida, Mitsuru
影响因子：
32.4
作者：
Christensen, Sean R.;Shupe, Jonathan;Shlomchik, Mark J.
通讯作者：
Shlomchik, Mark J.