TNF: Friend or foe in sepsis? A meta-analysis of experimental studies

Abstract Introduction Experimental studies in animals have yielded conflicting results on the role of Tumor Necrosis Factor (TNF) in sepsis, with some reporting protective effects and others reporting deleterious effects. To determine the factors that explain this discordance, a meta-analysis of the available literature was performed. Methods The study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol was registered with Prospero (CRD42020167384) prior to data collection. PubMed and Embase were the databases queried. Risk of bias was evaluated using the SYRCLE Risk of Bias Tool[1]. All animal studies investigating sepsis-related mortality and modified TNF signaling were considered eligible. The exclusion criteria were: lack of mortality data, 7-day mortality rates below 10% in both wild type and TNF-altered pathway animals, and absence of an English abstract. Protective and deleterious roles were assessed through multivariate analysis using a binary logistic regression model. Mortality data were pooled using a random-role model. Results A total of 175 studies were included that comprise a total of 760 experiments involving 19,899 animals. The main species used were mice (77%) and rats (21%). The most common method of TNF pathway modulation was TNF pathway inactivation, achieved using neutralizing antibodies or knock-out mice. TNF pathway inactivation was primarily associated with a deleterious role of TNF, whereas TNF injection was associated with a protective role. Lipopolysaccharide injection was the most used stimulus to establish a sepsis model (42%) and was strongly associated with a deleterious role of TNF. Conversely, live bacterial models, especially the cecal ligation and puncture (CLP) model, pneumonia, meningitis, and gastrointestinal infection, were associated with a protective role. This was particularly evident for Listeria monocytogenes, Klebsiella. pneumoniae, Salmonella species, Streptococcus pneumoniae and Candida spp. Conclusion: The role of TNF during infection varies depending on the experimental model used. Models that mimic clinical conditions, based on virulent bacteria that cause high mortality even at low inocula, demonstrated a protective role of TNF. Conversely, models based on LPS or low-pathogenic live bacteria, administered at doses well above physiological thresholds and combined with early antibiotic therapy, were associated with a deleterious role.