A systematic review and meta-analyses of interleukin-1 receptor associated kinase 3 (IRAK3) action on inflammation in in vivo models for the study of sepsis

Background 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-alpha 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. Methods 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. Results 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-alpha protein expression in humans were similar to rodent in vivo models. Meta-analyses confirmed the inhibitory effect of IRAK3 on TNF-alpha mRNA and protein expression after two challenges. Conclusions A negative correlation between IRAK3 and TNF-alpha 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.