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IL-17 Receptor Signaling Is Required to Control Polymicrobial Sepsis¹

Andressa Freitas^*, José C. Alves-Filho^*, Tatiana Victoni, Thomas Secher, Henrique P. Lemos^*, Fabiane Sônego^*, Fernando Q. Cunha^2,* and Bernhard Ryffel^2,,

^* Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Université d’Orl'eans and Centre National de la Recherche Scientifique, Molecular Immunology and Embryology, Transgenose Institute, Orleans, France; and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, Rondebosch, South Africa

Sepsis is a systemic inflammatory response resulting from the inability of the host to contain the infection locally. Previously, we demonstrated that during severe sepsis there is a marked failure of neutrophil migration to the infection site, which contributes to dissemination of infection, resulting in high mortality. IL-17 plays an important role in neutrophil recruitment. Herein, we investigated the role of IL-17R signaling in polymicrobial sepsis induced by cecal ligation and puncture (CLP). It was observed that IL-17R-deficient mice, subjected to CLP-induced non-severe sepsis, show reduced neutrophil recruitment into the peritoneal cavity, spread of infection, and increased systemic inflammatory response as compared with C57BL/6 littermates. As a consequence, the mice showed an increased mortality rate. The ability of IL-17 to induce neutrophil migration was demonstrated in vivo and in vitro. Beside its role in neutrophil recruitment to the infection focus, IL-17 enhanced the microbicidal activity of the migrating neutrophils by a mechanism dependent on NO. Therefore, IL-17 plays a critical role in host protection during 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 Fundação de Amparo à Pesquisa do Estado de São Paulo and Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico.

² Address correspondence and reprint requests to Prof. Fernando de Queiróz Cunha. Department of Pharmacology, School of Medicine of Ribeirão Preto, Avenida Bandeirantes, 3900, 14049-900-Ribeirão Preto, São Paulo, Brazil and Dr. Bernhard Ryffel, UMR6218, IEM, CNRS Transgenose Institute, 45071 Orleans, France. E-mail addresses: fdqcunha{at}fmrp.usp.br and bryffel{at}cnrs-orleans.fr

³ Abbreviations used in this paper: KC, keratinocyte-derived chemokine; BHI, brain-heart infusion; CLP, cecal ligation and puncture; NS-CLP, non-severe septic injury; S-CLP, severe septic injury; WT, wild type; KO, knockout; AG, aminoguanidine; AST, aspartate aminotransferase; ALT, alanine aminotransferase.