Crucial Role of TNF Receptors 1 and 2 in the Control of Polymicrobial Sepsis

Abstract

Sepsis is still a major cause of mortality in the intensive critical care unit and results from an overwhelming immune response to the infection. TNF signaling pathway plays a central role in the activation of innate immunity in response to pathogens. Using a model of polymicrobial sepsis by i.p. injection of cecal microflora, we demonstrate a critical role of TNFR1 and R2 activation in the deregulated immune responses and death associated with sepsis. A large and persistent production of TNF was found in wild-type (B6) mice. TNFR1/R2-deficient mice, compared with B6 mice, survive lethal polymicrobial infection with enhanced neutrophil recruitment and bacterial clearance in the peritoneal cavity. Absence of TNFR signaling leads to a decreased local and systemic inflammatory response with diminished organ injury. Furthermore, using TNFR1/R2-deficient mice, TNF was found to be responsible for a decrease in CXCR2 expression, explaining reduced neutrophil extravasation and migration to the infectious site, and in neutrophil apoptosis. In line with the clinical experience, administration of Enbrel, a TNF-neutralizing protein, induced however only a partial protection in B6 mice, with no improvement of clinical settings, suggesting that future TNF immunomodulatory strategies should target TNFR1 and R2. In conclusion, the present data suggest that the endogenous TNFR1/R2 signaling pathway in polymicrobial sepsis reduces neutrophil recruitment contributing to mortality and as opposed to pan-TNF blockade is an important therapeutic target for the treatment of polymicrobial sepsis.

Shedding of Tumor Necrosis Factor Receptor 1 Induced by Protein A Decreases Tumor Necrosis Factor Alpha Availability and Inflammation during Systemic Staphylococcus aureus Infection

“…In this regard, it is noteworthy that the majority of clinical trials attempting to modulate TNF-␣-driven immune responses have not taken into account during data analysis the potential differences in results according to the etiology of sepsis. Moreover, the most commonly used experimental model of sepsis is the murine cecal ligation and puncture model, in which peritonitis is induced by a mixture of anaerobic and facultatively anaerobic Gram-negative and Grampositive bacteria (50)(51)(52). Whereas this model might be very useful for understanding the pathophysiology of sepsis with a peritoneal focus, studies investigating the immune responses induced by single pathogens are also needed.…”

Toll-like receptor 9 activation in neutrophils impairs chemotaxis and reduces sepsis outcome*

“…GRKs phosphorylate serine/threonine residues on G-protein-coupled receptors, leading to receptor internalization and intracellular sorting, which results in either recycling or degradation of those receptors (10). Furthermore, the cell surface expression of CXCR2 is downregulated in severe sepsis by mechanisms that are dependent on the activation of toll-like receptors (TLRs) 2 and 4 (11)(12)(13), nitric oxide (14), tumor necrosis factor-α (15), and heme oxygenase products (16), all of which collectively induce the expression of GRK-2.…”

Angiopoietin-2 Enhances Survival in Experimental Sepsis Induced by Multidrug-ResistantPseudomonas aeruginosa

“…at ASPET Journals on May 10, 2018 jpet.aspetjournals.org Downloaded from with wild-type mice (Dharmana et al, 2002;Secher et al, 2009). Given the crucial role of TNF-␣ in Gram-negative sepsis, it can be explained, at least in part, why down-regulation of TNF-␣ production by Ang-2 confers significant survival benefit.…”