Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia.
PLoS One. 2022 Feb 15;17(2):e0263968. doi: 10.1371/journal.pone.0263968. eCollection 2022.
Interleukin-1 receptor associated kinase 3 (IRAK3) is a critical modulator of inflammation and is associated with endotoxin tolerance and sepsis. Although IRAK3 is known as a negative regulator of inflammation, several studies have reported opposing functions, and the temporal actions of IRAK3 on inflammation remain unclear. A systematic review and meta-analyses were performed to investigate IRAK3 expression and its effects on inflammatory markers (TNF-α and IL-6) after one- or two-challenge interventions, which mimic the hyperinflammatory and immunosuppression phases of sepsis, respectively, using human or animal in vivo models.
This systematic review and meta-analyses has been registered in the Open Science Framework (OSF) (Registration DOI: 10.17605/OSF.IO/V39UR). A systematic search was performed to identify in vivo studies reporting outcome measures of expression of IRAK3 and inflammatory markers. Meta-analyses were performed where sufficient data was available.
The search identified 7778 studies for screening. After screening titles, abstracts and full texts, a total of 49 studies were included in the systematic review. The review identified significant increase of IRAK3 mRNA and protein expression at different times in humans compared to rodents following one-challenge, whereas the increases of IL-6 and TNF-α protein expression in humans were similar to rodent in vivo models. Meta-analyses confirmed the inhibitory effect of IRAK3 on TNF-α mRNA and protein expression after two challenges.
A negative correlation between IRAK3 and TNF-α expression in rodents following two challenges demonstrates the association of IRAK3 in the immunosuppression phase of sepsis. Species differences in underlying biology affect the translatability of immune responses of animal models to human, as shown by the dissimilarity in patterns of IRAK3 mRNA and protein expression between humans and rodents following one challenge that are further influenced by variations in experimental procedures.
白细胞介素-1 受体相关激酶 3（IRAK3）是炎症的关键调节剂，与内毒素耐受和脓毒症有关。尽管 IRAK3 被认为是炎症的负调节剂，但有几项研究报告了相反的功能，IRAK3 对炎症的时间作用仍不清楚。本系统评价和荟萃分析旨在研究 IRAK3 的表达及其对炎症标志物（TNF-α 和 IL-6）的影响，这些标志物分别在人类或动物体内模型中模拟脓毒症的高炎症和免疫抑制阶段。
本系统评价和荟萃分析已在开放科学框架（OSF）中注册（注册号：10.17605/OSF.IO/V39UR）。进行了系统检索，以确定报告 IRAK3 和炎症标志物表达的体内研究。在有足够数据的情况下进行荟萃分析。
搜索确定了 7778 项用于筛选的研究。在筛选标题、摘要和全文后，共有 49 项研究纳入系统评价。该综述确定了与啮齿动物相比，人类在一次挑战后不同时间 IRAK3 mRNA 和蛋白表达的显著增加，而人类和啮齿动物体内模型中 IL-6 和 TNF-α 蛋白表达的增加相似。荟萃分析证实了 IRAK3 在两次挑战后对 TNF-α mRNA 和蛋白表达的抑制作用。
在两次挑战后，啮齿动物 IRAK3 和 TNF-α 表达之间的负相关表明 IRAK3 与脓毒症免疫抑制阶段有关。基础生物学的种间差异影响动物模型免疫反应对人类的可转化性，如在一次挑战后，人类和啮齿动物之间 IRAK3 mRNA 和蛋白表达模式的差异所示，进一步受到实验程序变化的影响。
