Abstract
BackgroundInterleukin-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.MethodsThis 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.ResultsThe 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.ConclusionsA 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.
Highlights
Sepsis is one of the major causes of mortality in intensive care units, with approximately 49 million incident cases worldwide in 2017, and 11 million sepsis-related deaths that account for 19.7% of all global deaths [1–3]
Abstracts and full texts, a total of 49 studies were included in the systematic review
The review identified significant increase of Interleukin-1 receptor associated kinase 3 (IRAK3) mRNA and protein expression at different times in humans compared to rodents following one-challenge, whereas the increases of IL-6 and tumour necrosis factor (TNF)-α protein expression in humans were similar to rodent in vivo models
Summary
Sepsis is one of the major causes of mortality in intensive care units, with approximately 49 million incident cases worldwide in 2017, and 11 million sepsis-related deaths that account for 19.7% of all global deaths [1–3]. Microbial infections activate innate immunity defences through the signalling pathways initiated by pattern recognition receptors including Toll-like receptors (TLRs) [5, 6]. The adaptor Myeloid differentiation primary response protein 88 (MyD88) is recruited to TLRs, to form a myddosome complex with interleukin-1 receptor associated kinase (IRAK) family members including IRAK1, IRAK2 and IRAK4 [5, 7]. IRAK4 activates IRAK1 or IRAK2 which dissociate from the complex and interact with tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6) [8]. TRAF6 triggers activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) transcription factor which induces transcription of inflammatory cytokine genes such as TNF-α and IL-6 [5]. IRAK3 inhibits the dissociation of IRAK1 or IRAK2 from myddosome complexes, disables the interaction of IRAK1 or IRAK2 with TRAF6, leading to downregulation of NF-κB activation [9, 12]. IRAK3 plays a crucial role in modulating TLR signalling pathways of innate immunity. A systematic review and metaanalyses 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
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