Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

doi:10.1128/IAI.00238-09

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Infection and Immunity, December 2009, p. 5651-5658, Vol. 77, No. 12
0019-9567/09/$08.00+0 doi:10.1128/IAI.00238-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

Frédéric Pène,¹^,2^,3 Emilie Courtine,¹^,2 Fatah Ouaaz,¹^,2 Benjamin Zuber,¹^,2^,3 Bertrand Sauneuf,¹^,2 Gonzalo Sirgo,¹^,2^, Christophe Rousseau,¹^,2 Julie Toubiana,¹^,2 Viviane Balloy,⁴^,5 Michel Chignard,⁴^,5 Jean-Paul Mira,¹^,2^,3 and Jean-Daniel Chiche¹^,2^,3^*

Département de Biologie Cellulaire, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France,¹ INSERM U567, Paris, France,² Réanimation Médicale, Hôpital Cochin, AP-HP, Paris, France,³ Défense Innée et Inflammation, Institut Pasteur, Paris, France,⁴ INSERM U874, Paris, France⁵

Received 2 March 2009/ Returned for modification 10 April 2009/ Accepted 18 September 2009

Depletion of dendritic cells (DC) in secondary lymphoid organsis a hallmark of sepsis-induced immune dysfunction. In thissetting, we investigated if Toll-like receptor (TLR)-dependentsignaling might modulate the maturation process and the survivalof DC. Using a model of sublethal polymicrobial sepsis inducedby cecal ligation and puncture, we investigated the quantitativeand functional features of spleen DC in wild-type, TLR2^–/–,TLR4^–/–, and TLR2^–/– TLR4^–/–mice. By 24 h, a decrease in the relative percentage of CD11c^highspleen DC occurred in wild-type mice but was prevented in TLR2^–/–,TLR4^–/–, and TLR2^–/– TLR4^–/–mice. In wild-type mice, sepsis dramatically affected both CD11c⁺CD8 ${alpha}$ ⁺ and CD11c⁺ CD8 ${alpha}$ ^– subsets. In all three types of knockoutmice studied, the CD11c⁺ CD8 ${alpha}$ ⁺ subset followed a depletion patternsimilar to that for wild-type mice. In contrast, the loss ofCD11c⁺ CD8 ${alpha}$ ^– cells was attenuated in TLR2^–/–and TLR4^–/– mice and completely prevented in TLR2^–/–TLR4^–/– mice. Accordingly, apoptosis of spleen DCwas increased in septic wild-type mice and inhibited in knockoutmice. In addition we characterized the functional features ofspleen DC obtained from septic mice. As shown by increased expressionof major histocompatibility complex class II and CD86, polymicrobialsepsis induced maturation of DC, with subsequent increased capacityto prime T lymphocytes, similarly in wild-type and knockoutmice. In response to CpG DNA stimulation, production of interleukin-12was equally impaired in DC obtained from wild-type and knockoutseptic mice. In conclusion, although dispensable for the DCmaturation process, TLR2 and TLR4 are involved in the mechanismsleading to depletion of spleen DC following polymicrobial sepsis.

* Corresponding author. Mailing address: Département de Biologie Cellulaire, Institut Cochin, 22 rue Méchain, 75014 Paris, France. Phone: 33 1 40 51 64 44. Fax: 33 1 40 51 64 54. E-mail: jean-daniel.chiche{at}cch.aphp.fr

Published ahead of print on 5 October 2009.

Editor: F. C. Fang

Present address: ICU, Hospital Verge de la Cinta, Tortosa (Tarragona),Spain.