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* Molecular Immunology and Embryology, University of Orleans and Centre National de la Recherche Scientifique, France;
Regional Hospital of Orleans, Orleans, France;
Cardiothoracic Pharmacology, Pharmacology and Toxicology, National Heart and Lung Institute, Imperial College of London, London, United Kingdom;
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil;
¶ Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom; and
|| Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Republic of South Africa
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Centre National de la Recherche Scientifique and the Medical Research Foundation (Fondation pour la Recherche Médicale Francais) and the European Union (to T.S.).
2 Address correspondence and reprint requests to Dr. Bernhard Ryffel, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 6218 Molecular Immunology and Embryology, Institut de Transgénose, 3B rue de la Férollerie, 45071 Orleans, Cedex 2, France. E-mail address: bryffel{at}cnrs-orleans.fr
3 Abbreviations used in this paper: LT, lymphotoxin; PLF, peritoneal lavage fluid; KC, keratinocyte-derived chemokine; MPO, myeloperoxidase; MODS, multiple organ dysfunction syndrome; HTAB, hexadecyltrimethyl ammonium bromide; sTNFR1/sTNRF2, soluble TNFR1/TNFR2.
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