ABSTRACT
Introduction: Reverting Systemic inflammatory response syndromes (SIRS), particularly sepsis, is a huge challenge of contemporary medicine. Inhibition of the cytokine tumor necrosis factor alpha (TNFα), originally considered as a mediator in sepsis, has led to frustrating results. Equally so, glucocorticoids (GCs), renowned for their role in numerous inflammatory diseases, remain controversial in sepsis.
Areas covered: We discuss how, in SIRS, the intestinal epithelium is a critical TNF-responsive target. Inhibition of TNF receptor 1 (TNFR1), rather than TNF, may be a more targeted and safe therapeutic approach. In intestinal epithelial cells (IECs), a strong interplay between GCs and TNF exists. Addressing GCs in these cells is crucial in SIRS and sepsis and would avoid dose-limiting off-target effects, for example on immune cells and phagocytes.
Expert opinion: The targeting of TNFR1 specifically at the level of IECs, potentially combined with IEC-specific stimulation of GR, could lead to a more safe and targeted treatment for SIRS and sepsis.
Article Highlights
Disturbances of intestinal homeostasis have been shown to form the basis of numerous inflammatory, infectious, metabolic, and even psychiatric disorders.
The gut is hypothesized to play a central role in the progression of sepsis.
TNF has a diverse, important effect on all components of the intestinal barrier
TNF toxicity, lethality, and intestinal barrier problems are mediated by three mechanisms that may be linked in a sequential manner: endoplasmic reticulum (ER) stress, goblet- and Paneth cell dysfunction and bacterial translocation.
Specific targeting of TNFR1 offers a safer approach than TNF inhibition.
Glucocorticoid treatment can normalize TNF-induced intestinal barrier dysfunction.
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Acknowledgements
‘The author’s work was supported by the Agency for Innovation of Science and Technology in Flanders (IWT), the Research Council of Ghent University (GOA program), the Research Foundation Flanders (FWO Vlaanderen), COST action BM1402 and the Interuniversity Attraction Poles Program of the Belgian Science Policy (IAP-VI-18).
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose