Mechanisms of action of anti-inflammatory proteins and peptides with anti-TNF-alpha activity and their effects on the intestinal barrier: A systematic review

Abstract

Several studies in animal models of intestinal inflammation have been performed with the aim of understanding the mechanisms of action of anti-inflammatory proteins and peptides that reduce TNF-α. In order to present the best targets, effects and strategies for the treatment of intestinal inflammation in experimental models, this systematic review (SR) aimed to answer the following question: what are the mechanisms of action of molecules with anti-TNF-α activity on the intestinal barrier? The SR protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO, number CRD42019131862) and guided by the methodological procedures used for the elaboration of the SR. Articles that were part of the SR were selected considering the eligibility criteria according to the PICO (Population, Intervention, Comparison/Control and Outcomes) and were searched in the PubMed, Scopus, Web of Science, Excerpta Medica Database (EMBASE) and ScienceDirect databases. Twenty-five articles reporting studies in rats and mice were selected and the risk of bias was assessed using the tool from the SYstematic Review Center for Laboratory Animal Experimentation (SYRCLE). A descriptive synthesis of the results obtained was carried out. Based on the results, the anti-inflammatory molecules that reduced TNF-α acted mainly on the TNF-TNFR1/TNFR2 and TLR4/MD2 complex signaling pathways, and consequently on the NF-κB pathway. This improved the aspects of the inflammatory diseases studied. In addition, these mechanisms also improved the macroscopic, histological and permeability aspects in the intestine of the animals. These findings point to the potential of protein and peptide molecules that act on inflammatory pathways for medical applications with specific and promising strategic targets, aiming to improve inflammatory diseases that affect the intestine. This systematic review also highlights the need for more details during the methodological description of preclinical studies, since this was a limitation found.

Fig 1. PRISMA flow diagram.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) flowchart [13] of the articles included in the systematic review, aiming to answer the question: what are the mechanisms of action of molecules with anti-tnf-α activity on the intestinal barrier?

Fig 2. Assessment of the risk of bias of the studies included in the systematic review aiming to answer the question: What are the mechanisms of action of molecules with anti-tnf-α activity on the intestinal barrier?

The articles were evaluated based on the tool of the SYstematic Review Center for Laboratory Animal Experimentation (SYRCLE), developed by Hooijmans et al. [16].

Fig 3. Schematic illustration of a hypothetical immune cell, presenting the main mechanisms discussed about the action of anti-inflammatory proteins and peptides with anti-TNF-alpha activity that act on the intestinal barrier.

The figure was built using the Servier Medical Art images (smart.servier.com). IFN: interferon, IL: interleukin; LBP: LPS-binding protein; LPS: lipopolysaccharide; TGF: transforming growth factor; TLR4: tool like receptor 4; TNF-α: tumor necrosis factor alpha; TNFR: tumor necrosis factor alpha receptor.