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Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets
International Immunopharmacology ( IF 5.6 ) Pub Date : 2020-10-12 , DOI: 10.1016/j.intimp.2020.107087
V. Kumar

Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators [cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS)], which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role.



中文翻译:

败血症相关细胞因子风暴中的Toll样受体及其内源性负调节剂作为未来的免疫调节靶标

细胞因子风暴在各种系统性急性感染期间产生,包括败血症和称为COVID-19(严重)的当前大流行,引起毁灭性的炎症,包括多器官衰竭或多器官功能障碍综合征(MODS)和患者死亡。Toll样受体(TLR)是免疫细胞以及非免疫细胞(包括神经元)表达的主要模式识别受体(PRR)之一,它们在产生细胞因子风暴中起关键作用。他们识别微生物相关的分子模式(MAMP,由病原体表达)和损伤或死亡相关的分子模式(DAMP;由受损/杀死的宿主细胞释放和/或表达)。识别MAMP和DAMP后,TLR激活下游信号传导途径,释放出几种促炎性介质[细胞因子,趋化因子,干扰素,和活性氧和氮(ROS或RNS)],可引起急性炎症,从而控制病原体并修复损害。由于宿主的遗传组成和/或病原体由于逃避机制而导致的病原体持续存在,导致过度反应的诱导可能导致严重的全身性炎症,即对细胞因子风暴和器官功能障碍产生反应的败血症。TLR诱导的炎症反应的激活与几种负反馈机制的诱导紧密相关,这些负反馈机制可发挥作用以结束反应并维持免疫稳态。这项最新的综述描述了TLR信号在败血症相关性细胞因子风暴发作中的重要性,并讨论了TLR信号通路中各种宿主衍生的内源性负调控因子。该主题非常重要,因为在这些负反馈机制中涉及大量基因和过程。这些分子和机制可用于开发针对细胞因子风暴相关疾病的新型治疗药物,其中包括败血症,严重的COVID-19和其他炎症性疾病,其中TLR信号在其中起着重要作用。

更新日期:2020-10-17
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