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

Molecular Immunology and Embryology, University of Orleans and Centre National de la Recherche Scientifique, France.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 182(12):7855-64. DOI: 10.4049/jimmunol.0804008
Source: PubMed


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.

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    • "Experimental models of sepsis have also shown increased levels of TNFα in the serum preceding organ failure34. TNFα is the major contributor to organ failure and death in the progression of sepsis35, and anti-TNF-mAb therapy (Afelimomab) in clinical trials has had a little positive effect21. During sepsis in vivo, the upregulation of proinflammatory cytokines initiates and contributes to organ dysfunction syndrome. "
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