Should we target TNF receptors in the intestinal epithelium with glucocorticoids during systemic inflammation?

Introduction: Reverting Systemic inflammatory response syndromes (SIRS), particularly sepsis, is a huge challenge of contemporary medicine. Inhibition of the cytokine tumor necrosis factor alpha (TNF alpha), 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.